Inhibitors of EGFR and/or HER2 and methods of use

ABSTRACT

The application relates to a compound having Formula X: which modulates the activity of HER2 and/or a mutant thereof, and/or EGFR and/or a mutant thereof, a pharmaceutical composition comprising the compound, and a method of treating or preventing a disease in which HER2 and/or a mutant thereof, and/or EGFR and/or a mutant thereof, plays a role.

RELATED APPLICATION

This application claims priority to, and the benefit of, U.S.Provisional Application No. 62/552,531, filed on Aug. 31, 2017, thecontents of which are incorporated herein by reference in theirentirety.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

This invention was made with government support under Grant Nos. R01CA116020 and P01 CA154303 awarded by the National Institutes of Health.The government has certain rights in the invention.

BACKGROUND

EGFR tyrosine kinase inhibitors (TKIs), such as gefitinib, have beenshown to be effective therapeutic agents for patients with non-smallcell lung cancer (NSCLC) that harbors somatic activating mutations inEGFR. However, responders typically relapse 6-19 months after takingEGFR TKIs as a consequence of becoming resistant to the inhibitors. Themost common resistance mutation occurs at the gatekeeper T790M position.Another mechanism of resistance involves upregulation of alternativesignal transduction pathways.

Several EGFR gene mutations (e.g., G719X, exon 19 deletions/insertions,L858R, and L861Q) predict favorable responses to EGFR TKIs in advancedNSCLC. In addition, the acquired gefitinib resistant mutation, T790M, istreatable with a third generation EGFR inhibitor, osimertinib. However,EGFR exon 20 insertion mutations (˜10% of all EGFR mutations) aregenerally associated with insensitivity to available TKIs (gefitinib,erlotinib, afatinib, and osimertinib). One exception is theEGFR-A763_Y764insFQEA insertion which is highly sensitive to EGFR TKIsin vitro, and patients whose NSCLCs harbor this mutation respond toerlotinib.

Human epidermal growth factor receptor 2 (HER2) is another member of thehuman epidermal growth factor receptor family. HER2 mutations, whichmainly consist of exon 20 insertion mutations, have been reported inapproximately 1-4% of NSCLC patients. Phase I and II clinical datademonstrated that patients harboring HER2 mutations partially respondedto treatment with afatinib, neratinib, or dacomitinib. Although patientswith HER2 insYVMA have reported durable responses to afatinib as asingle agent, a recent phase II trial of dacomitinib showed no responsein all 13 patients with HER2 insYVMA (A775_G776insYVMA), whichrepresents up to 80% of HER2 mutations in lung cancers.

Thus, novel therapies for patients with EGFR mutations (e.g., exon 20insertion mutations) are desired. Further, compounds possessing activityagainst HER2 mutations are needed, as they may have extended utility intreating tumors harboring such mutations.

SUMMARY

The present application features a class of novel small moleculecompounds that inhibit epidermal growth factor receptor tyrosine kinase(EGFR) and/or human epidermal growth factor receptor 2 (HER2). In someembodiments, the compounds are capable of modulating (e.g., inhibitingor decreasing) EGFR and/or HER2 that are resistant to other drugs, e.g.,EGFR and/or HER2 with exon 20 mutations, exon 19 mutations, gefitinibresistant T790M mutation, and/or exon 20 insertion mutations.

In one aspect, the present application relates to a compound of FormulaX:

or a pharmaceutically acceptable salt thereof, wherein X₁, X₂, X₃, X₄,R₁, R₃, R₄, and R₅ are each described herein in detail below.

In one aspect, the present application relates to a compound of FormulaI′:

or a pharmaceutically acceptable salt thereof, wherein R₁, R₂, R₃, R₄,R₅, and R₆ are each described herein in detail below.

In another aspect, the present application relates to a pharmaceuticalcomposition comprising a compound of any one of the formulae describedherein, or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier.

In another aspect, the present application relates to a kit comprising acompound of the present application, or a pharmaceutically acceptablesalt thereof.

In another aspect, the present application relates to a method ofmodulating (e.g., inhibiting or decreasing) EGFR or a mutant thereof,comprising administering to a subject in need thereof an effectiveamount of a compound of the present application, or a pharmaceuticallyacceptable salt thereof.

In another aspect, the present application relates to a method ofmodulating (e.g., inhibiting or decreasing) HER2 or a mutant thereof,comprising administering to a subject in need thereof an effectiveamount of a compound of the present application, or a pharmaceuticallyacceptable salt thereof.

In another aspect, the present application relates to a method ofmodulating (e.g., inhibiting or decreasing) EGFR or a mutant thereof andHER2 or a mutant thereof, comprising administering to a subject in needthereof an effective amount of a compound of the present application, ora pharmaceutically acceptable salt thereof.

In another aspect, the present application relates to a method oftreating or preventing a disease or disorder, such as a kinase mediateddisease or disorder, comprising administering to a subject in needthereof an effective amount of a compound of the present application, ora pharmaceutically acceptable salt thereof.

In another aspect, the present application relates to a method oftreating or preventing a disease or disorder resistant to an EGFRtargeted therapy and/or a HER2 targeted therapy, such as a therapy withgefitinib or erlotinib, comprising administering to a subject in needthereof an effective amount of a compound of the present application, ora pharmaceutically acceptable salt thereof.

In another aspect, the present application relates to a method oftreating or preventing cancer, wherein the cancer cell comprises amutant EGFR and/or a mutant HER2, comprising administering to a subjectin need thereof an effective amount of a compound of the presentapplication, or a pharmaceutically acceptable salt thereof.

In another aspect, the present application relates to a method oftreating or preventing a disease or disorder, such as a kinase mediateddisease or disorder, in a subject in need thereof, wherein the subjectis identified as being in need of modulation (e.g., inhibition ordecrease) of EGFR or a mutant thereof and/or HER2 or a mutant thereoffor the treatment or prevention of the disease or disorder, comprisingadministering to the subject an effective amount of a compound of thepresent application, or a pharmaceutically acceptable salt thereof.

In another aspect, the present application relates to a compound of thepresent application for modulating (e.g., inhibiting or decreasing) EGFRor a mutant thereof and/or HER2 or a mutant thereof; for treating orpreventing a disease or disorder, such as a kinase mediated disease ordisorder; for treating or preventing a disease or disorder resistant toan EGFR targeted therapy and/or a HER2 targeted therapy; for treating orpreventing cancer, wherein the cancer cell comprises a mutant EGFRand/or a mutant HER2; or for treating or preventing a disease ordisorder, such as a kinase mediated disease or disorder in a subjectidentified as being in need of modulation (e.g., inhibition or decrease)of EGFR or a mutant thereof and/or HER2 or a mutant thereof for thetreatment or prevention of the disease or disorder.

In another aspect, the present application relates to a compound of thepresent application for use in the modulation (e.g., inhibition ordecrease) of EGFR or a mutant thereof and/or HER2 or a mutant thereof;in the treatment or prevention of a disease or disorder, such as akinase mediated disease or disorder; in the treatment or prevention of adisease or disorder resistant to an EGFR targeted therapy and/or a HER2targeted therapy; in the treatment or prevention of cancer, wherein thecancer cell comprises a mutant EGFR and/or a mutant HER2; or in thetreatment or prevention of a disease or disorder, such as a kinasemediated disease or disorder in a subject identified as being in need ofmodulation (e.g., inhibition or decrease) of EGFR or a mutant thereofand/or HER2 or a mutant thereof for the treatment or prevention of thedisease or disorder.

In another aspect, the present application relates to use of a compoundof the present application in the modulation (e.g., inhibition ordecrease) of EGFR or a mutant thereof and/or HER2 or a mutant thereof;in the treatment or prevention of a disease or disorder, such as akinase mediated disease or disorder; in the treatment or prevention of adisease or disorder resistant to an EGFR targeted therapy and/or a HER2targeted therapy; in the treatment or prevention of cancer, wherein thecancer cell comprises a mutant EGFR and/or a mutant HER2; or in thetreatment or prevention of a disease or disorder, such as a kinasemediated disease or disorder in a subject identified as being in need ofmodulation (e.g., inhibition or decrease) of EGFR or a mutant thereofand/or HER2 or a mutant thereof for the treatment or prevention of thedisease or disorder.

In another aspect, the present application relates to a compound of thepresent application for use in the manufacture of a medicament for themodulation (e.g., inhibition or decrease) of EGFR or a mutant thereofand/or HER2 or a mutant thereof; for the treatment or prevention of adisease or disorder, such as a kinase mediated disease or disorder; forthe treatment or prevention of a disease or disorder resistant to anEGFR targeted therapy and/or a HER2 targeted therapy; for the treatmentor prevention of cancer, wherein the cancer cell comprises a mutant EGFRand/or a mutant HER2; or for the treatment or prevention of a disease ordisorder, such as a kinase mediated disease or disorder in a subjectidentified as being in need of modulation (e.g., inhibition or decrease)of EGFR or a mutant thereof and/or HER2 or a mutant thereof for thetreatment or prevention of the disease or disorder.

In another aspect, the present application relates to use of a compoundof the present application in the manufacture of a medicament for themodulation (e.g., inhibition or decrease) of EGFR or a mutant thereofand/or HER2 or a mutant thereof; for the treatment or prevention of adisease or disorder, such as a kinase mediated disease or disorder; forthe treatment or prevention of a disease or disorder resistant to anEGFR targeted therapy and/or a HER2 targeted therapy, for the treatmentor prevention of cancer, wherein the cancer cell comprises a mutant EGFRand/or a mutant HER2 or for the treatment or prevention of a disease ordisorder, such as a kinase mediated disease or disorder in a subjectidentified as being in need of modulation (e.g., inhibition or decrease)of EGFR or a mutant thereof and/or HER2 or a mutant thereof for thetreatment or prevention of the disease or disorder.

The details of the application are set forth in the accompanyingdescription below. Although methods and materials similar or equivalentto those described herein can be used in the practice or testing of thepresent application, illustrative methods and materials are nowdescribed. In the case of conflict, the present specification, includingdefinitions, will control. In addition, the materials, methods, andexamples are illustrative only and are not intended to be limiting.Other features, objects, and advantages of the application will beapparent from the description and from the claims. In the specificationand the appended claims, the singular forms also include the pluralunless the context clearly dictates otherwise. Unless defined otherwise,all technical and scientific terms used herein have the same meaning ascommonly understood by one of ordinary skill in the art to which thisapplication belongs. All patents and publications cited in thisspecification are incorporated herein by reference in their entireties.

The contents of all references (including literature references, issuedpatents, published patent applications, and co-pending patentapplications) cited throughout this application are hereby expresslyincorporated herein in their entireties by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a Western blot showing decrease in EGFR phosphorylation inwild-type EGFR, EGFR InsGY, or EGFR InsSVD transformed Ba/F3 cellstreated with the indicated concentrations of afatinib or Compound 2.

FIG. 2A is a plot comparing effects of afatinib and Compound 2 onDFCI127c cell growth (measured by relative absorbance); FIG. 2B is aplot comparing effects of afatinib and Compound 2 on DFCI362JC cellgrowth (measured by relative absorbance); and FIG. 2C is a plotcomparing effects of afatinib and Compound 2 on DFCI58-229 cell growth(measured by relative absorbance). All results were obtained after thecells were treated with afatinib or Compound 2 for 72 hours and wereaveraged between 6 to 12 wells. Data were normalized to untreated cellsand displayed graphically using GraphPad Prism (GraphPad Software,Inc.). The growth curves were fitted using a nonlinear regression modelwith sigmoidal dose response.

FIG. 3 is a Western blot showing levels of phosphorylated EGFR (p-EGFR),total EGFR, phosphorylated Akt (p-Akt), total Akt, phosphorylated ERK(p-ERK), total ERK, and HSP90 in DFCI127c and DFCI362JC cells treatedwith the indicated concentrations of afatinib or Compound 2.

DETAILED DESCRIPTION

Compounds of the Application

The present application relates to a compound of Formula X:

or a pharmaceutically acceptable salt thereof, wherein:

X₁ is CH or N;

X₂ is CR₆ or N;

X₃ is —NR₂—C(O)— or —N═CR₂—;

X₄ is NH, O, or S;

R₁ is H, C₁-C₄ alkyl, C(O)—(C₁-C₄ alkyl), C₃-C₈ cycloalkyl, heterocyclylcomprising one or two 5- or 6-membered rings and 1-4 heteroatomsselected from N, O, and S, phenyl, or heteroaryl comprising one or two5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S,wherein the cycloalkyl, heterocyclyl, phenyl, or heteroaryl isoptionally substituted with one or more R_(a1); and R₂ is Q-R₂′, whereinQ is (CH₂)₀₋₃ and R₂′ is C₃-C₈ cycloalkyl, heterocyclyl comprising one4- to 7-membered ring and 1-3 heteroatoms selected from N, O, and S,phenyl, or heteroaryl comprising one 5- or 6-membered ring and 1-3heteroatoms selected from N, O, and S, wherein the cycloalkyl,heterocyclyl, phenyl, or heteroaryl is substituted with one or moreR_(b1), provided that when Q is (CH₂)₀, R₂′ is pyrrolidinyl, and R₃ isphenyl or phenyl substituted with halogen, then R₁ is not substitutedphenyl; or

R₁ is phenyl or heteroaryl comprising one 5- or 6-membered ring and 1-3heteroatoms selected from N, O, and S, wherein the phenyl or heteroarylis substituted with one or more R_(a2); and R₂ is H, NH₂, C₁-C₄ alkyl,or C₃-C₆ cycloalkyl, wherein the alkyl or cycloalkyl is optionallysubstituted with one or more R_(b2);

R₃ is C₆-C₁₀ aryl or heteroaryl comprising one or two 5- or 6-memberedrings and 1-4 heteroatoms selected from N, O, and S, wherein the aryl orheteroaryl is optionally substituted with one or more R₇;

R₄, R₅, and R₆ are each independently H or C₁-C₄ alkyl;

each R₇ is independently C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkoxy, OH, halogen, CN, or NR_(n3)R_(n4);

each R_(a1) is independently C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkoxy, OH, halogen, NH—C(O)—(C₂-C₄ alkenyl), NR_(n3)R_(n4),O—(CH₂)₁₋₄—NR_(n1)R_(n2), NR_(n1)—(CH₂)₁₋₄—NR_(n1)R_(n2), C₃-C₈cycloalkyl, heterocyclyl comprising one or two 4- to 6-membered ringsand 1-4 heteroatoms selected from N, O, and S, phenyl, or heteroarylcomprising one or two 5- or 6-membered rings and 1-4 heteroatomsselected from N, O, and S, wherein the alkyl, cycloalkyl, heterocyclyl,phenyl, or heteroaryl is optionally substituted with one or more R₁₁;

each R_(b1) is independently W, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy, C₁-C₆ haloalkoxy, OH, halogen, or NR_(n3)R_(n4), wherein atleast one R_(b1) is W, or when the at least one R_(b1) is bonded to anitrogen atom in a heterocyclyl ring comprising at least one nitrogenatom, R_(b1) is C(O)R₉;

each R_(a2) is independently W, NH—C(O)—(C₁-C₄ alkyl), C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, OH, halogen,NR_(n3)R_(n4), O—(CH₂)₀₋₄—NR_(n1)R_(n2), NR_(n1)—(CH₂)₁₋₄—NR_(n1)R_(n2),C₃-C₈ cycloalkyl, heterocyclyl comprising one or two 4- to 6-memberedrings and 1-4 heteroatoms selected from N, O, and S, phenyl, orheteroaryl comprising one or two 5- or 6-membered rings and 1-4heteroatoms selected from N, O, and S, wherein the alkyl, cycloalkyl,heterocyclyl, phenyl, or heteroaryl is optionally substituted with oneor more R₁₁, wherein at least one R_(a2) is W;

each R_(b2) is independently C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkoxy, OH, halogen, NR_(n3)R_(n4), or heterocyclyl comprisingone 4- to 6-membered rings and 1 or 2 heteroatoms selected from N, O,and S;

each R₈ is independently H or C₁-C₄ alkyl;

each R₉ is independently C₂-C₄ alkenyl optionally substituted with oneor more R₁₀;

each R₁₀ is independently NR_(n3)R_(n4);

each R₁₁ is independently C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkoxy, OH, halogen, CN, NR_(n3)R_(n4), C₃-C₈ cycloalkyl, orheterocyclyl comprising one or two 4- to 6-membered rings and 1-4heteroatoms selected from N, O, and S, wherein the cycloalkyl orheterocyclyl is optionally substituted with one or more C₁-C₆ alkyl,halogen, or C(O)—(C₂-C₄ alkenyl);

each R_(n1) and each R_(n2) are independently H or C₁-C₄ alkyl, orR_(n1) and R_(n2), together with the nitrogen atom to which they arebonded, form a 4- to 7-membered heterocyclyl ring comprising 1 to 3heteroatoms selected from N, O, and S, wherein the heterocyclyl isoptionally substituted with one or more C₁-C₆ alkyl;

each R_(n3) and each R_(n4) are independently H or C₁-C₄ alkyl;

W is NR₈C(O)R₉, C(O)R₉, or is of formula:

L₃ is a bond or an optionally substituted C₁-C₄ hydrocarbon chain,optionally wherein one or more carbon units of the hydrocarbon chain areindependently replaces with —C═O—, —O—, —S—, —NR_(L3a)—,—NR_(L3a)C(═))—, C(═C)NR_(L3a)—, —SC(═O)—, —C(═O)S—, —OC(═O)—, —C(═O)O—,—NR_(L3a)C(═S)—, —C(═S)NR_(L3a)—, trans-CR_(L3b)═CR_(L3b)—,cis-CR_(L3b)═CR_(L3b)—, —C≡C—, —S(═O)—, —S(═O)O—, —OS(═O)—,—S(═O)NR_(L3a)—, —NR_(L3a)S(═O)—, —S(═O)₂—, —S(═O)₂O—, —OS(═O)₂—,—S(═O)₂NR_(L3a)—, or —NR_(L3a)S(═O)₂—;

R_(L3a) is H, optionally substituted C₁-C₆ alkyl, or a nitrogenprotecting group;

each R_(L3b) is independently H, halogen, optionally substituted C₁-C₆alkyl, optionally substituted C₂-C₆ alkenyl, optionally substitutedC₂-C₆ alkynyl, optionally substituted C₃-C₈ cycloalkyl, optionallysubstituted heterocyclyl comprising one or two 5- or 6-membered ringsand 1-4 heteroatoms selected from N, O, and S, optionally substitutedC₆-C₁₀ aryl, or optionally substituted heteroaryl comprising one or two5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, ortwo R_(L3b) groups are joined to form an optionally substituted C₃-C₈carbocycle or optionally substituted 4- to 7-membered heterocyclyl ringcomprising 1 to 3 heteroatoms selected from N, O, and S:

L₄ is a bond or an optionally substituted C₁-C₆ hydrocarbon chain:

each of R_(E1), R_(E2), and R_(E3) is independently H, halogen,optionally substituted C₁-C₆ alkyl, optionally substituted C₂-C₆alkenyl, optionally substituted C₂-C₆ alkynyl, optionally substitutedC₃-C₈ cycloalkyl, optionally substituted heterocyclyl comprising one ortwo 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, andS, optionally substituted C₆-C₁₀ aryl, or optionally substitutedheteroaryl comprising one or two 5- or 6-membered rings and 1-4heteroatoms selected from N, O, and S, CN, CH₂OR_(EE), CH₂N(R_(EE))₂,CH₂SR_(EE), OR_(EE), N(R_(EE))₂, Si(R_(EE))₃, or SR_(EE), or R_(E1) andR_(E3), or R_(E2) and R_(E3), or R_(E1) and R_(E2) are joined to form anoptionally substituted C₃-C₈ carbocycle or optionally substituted 4- to7-membered heterocyclyl ring comprising 1 to 3 heteroatoms selected fromN, O, and S;

each R_(EE) is independently H, optionally substituted C₁-C₆ alkyl,optionally substituted C₁-C₆ alkoxy, optionally substituted C₂-C₆alkenyl, optionally substituted C₂-C₆ alkynyl, optionally substitutedC₃-C₈ cycloalkyl, optionally substituted heterocyclyl comprising one ortwo 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, andS, optionally substituted C₆-C₁₀ aryl, or optionally substitutedheteroaryl comprising one or two 5- or 6-membered rings and 1-4heteroatoms selected from N, O, and S, or two R_(EE) groups are joinedto form an optionally substituted 4- to 7-membered heterocyclyl ringcomprising 1 to 3 heteroatoms selected from N, O, and S;

R_(E5) is halogen:

R_(E6) is H, optionally substituted C₁-C₆ alkyl, or a nitrogenprotecting group;

each Y is independently O, S, or NR_(E7);

R_(E7) is H, optionally substituted C₁-C₆ alkyl, or a nitrogenprotecting group:

a is 1 or 2; and

each z is independently 0, 1, 2, 3, 4, 5, or 6.

In one embodiment, X₁ is CH.

In one embodiment, X₁ is N.

In one embodiment, X₂ is CR₆.

In one embodiment, X₂ is N.

In one embodiment, X₃ is —NR₂—C(O)—.

In one embodiment, X₃ is —N═CR₂—.

In one embodiment, X₁ is N, X₂ is CR₆, and X₃ is —NR₂—C(O)—. In afurther embodiment, R₆ is H.

In one embodiment, X₁ is N, X₂ is CR₆, and X₃ is —N═CR₂—. In a furtherembodiment, R₂ is C₁-C₄ alkyl. In a further embodiment, R₂ is methyl. Inanother further embodiment, R₂ is NH₂. In a further embodiment, R₆ is H.

In one embodiment, X₁ is N, X₂ is N, and X₃ is —NR₂—C(O)—.

In one embodiment, X₁ is CH, X₂ is N, and X₃ is —NR₂—C(O)—.

In one embodiment, X₁, X₂, or X₃, or any combination thereof, is asdescribed above, and X₄ is NH.

In one embodiment, X₁, X₂, or X₃, or any combination thereof, is asdescribed above, and X₄ is O.

In one embodiment, X₁, X₂, or X₃, or any combination thereof, is asdescribed above, and X₄ is S.

In one embodiment, X₁ is N, X₂ is CR₆, X₃ is —NR₂—C(O)—, and X₄ is NH.In a further embodiment, R₆ is H. In a further embodiment, R₂ is C₁-C₄alkyl. In a further embodiment, R₂ is methyl.

In one embodiment, the compound is of Formula I′:

or a pharmaceutically acceptable salt thereof, wherein:

R₁ is H, C₁-C₄ alkyl, C(O)—(C₁-C₄ alkyl), C₃-C₈ cycloalkyl, heterocyclylcomprising one or two 5- or 6-membered rings and 1-4 heteroatomsselected from N, O, and S, phenyl, or heteroaryl comprising one or two5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S,wherein the cycloalkyl, heterocyclyl, phenyl, or heteroaryl isoptionally substituted with one or more R_(a1); and R₂ is Q-R₂′, whereinQ is (CH₂)₀₋₃ and R₂′ is C₃-C₈ cycloalkyl, heterocyclyl comprising one4- to 7-membered ring and 1-3 heteroatoms selected from N, O, and S,phenyl, or heteroaryl comprising one 5- or 6-membered ring and 1-3heteroatoms selected from N, O, and S, wherein the cycloalkyl,heterocyclyl, phenyl, or heteroaryl is substituted with one or moreR_(b1), provided that when Q is (CH₂)₀, R₂′ is pyrrolidinyl, and R₃ isphenyl or phenyl substituted with halogen, then R₁ is not substitutedphenyl; or

R₁ is phenyl or heteroaryl comprising one 5- or 6-membered ring and 1-3heteroatoms selected from N, O, and S, wherein the phenyl or heteroarylis substituted with one or more R_(a2); and R₂ is H, C₁-C₄ alkyl, orC₃-C₆ cycloalkyl, wherein the alkyl or cycloalkyl is optionallysubstituted with one or more R_(b2);

R₃ is C₆-C₁₀ aryl or heteroaryl comprising one or two 5- or 6-memberedrings and 1-4 heteroatoms selected from N, O, and S, wherein the aryl orheteroaryl is optionally substituted with one or more R₇;

R₄, R₅, and R₆ are each independently H or C₁-C₄ alkyl;

each R₇ is independently C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkoxy, OH, halogen, CN, or NR_(n3)R_(n4);

each R_(a1) is independently C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkoxy, OH, halogen, NH—C(O)—(C₂-C₄ alkenyl), NR_(n3)R_(n4),O—(CH₂)₁₋₄—NR_(n1)R_(n2), NR_(n1)—(CH₂)₁₋₄—NR_(n1)R_(n2), C₃-C₈cycloalkyl, heterocyclyl comprising one or two 4- to 6-membered ringsand 1-4 heteroatoms selected from N, O, and S, phenyl, or heteroarylcomprising one or two 5- or 6-membered rings and 1-4 heteroatomsselected from N, O, and S, wherein the alkyl, cycloalkyl, heterocyclyl,phenyl, or heteroaryl is optionally substituted with one or more R₁₁;

each R_(b1) is independently W, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy, C₁-C₆ haloalkoxy, OH, halogen, or NR_(n3)R_(n4), wherein atleast one R_(b1) is W, or when the at least one R_(b1) is bonded to anitrogen atom in a heterocyclyl ring comprising at least one nitrogenatom, R_(b1) is C(O)R₉;

each R_(a2) is independently W, NH—C(O)—(C₁-C₄ alkyl), C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, OH, halogen,NR_(n3)R_(n4), O—(CH₂)₀₋₄—NR_(n1)R_(n2), NR_(n1)—(CH₂)₁₋₄—NR_(n1)R_(n2),C₃-C₈ cycloalkyl, heterocyclyl comprising one or two 4- to 6-memberedrings and 1-4 heteroatoms selected from N, O, and S, phenyl, orheteroaryl comprising one or two 5- or 6-membered rings and 1-4heteroatoms selected from N, O, and S, wherein the alkyl, cycloalkyl,heterocyclyl, phenyl, or heteroaryl is optionally substituted with oneor more R₁₁, wherein at least one R_(a2) is W:

-   -   each R_(b2) is independently C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆        alkoxy, C₁-C₆ haloalkoxy, OH, halogen, NR_(n3)R_(n4), or        heterocyclyl comprising one 4- to 6-membered rings and 1 or 2        heteroatoms selected from N, O, and S;

each R₈ is independently H or C₁-C₄ alkyl;

each R₉ is independently C₂-C₄ alkenyl optionally substituted with oneor more R₁₀;

each R₁₀ is independently NR_(n3)R₄;

each R₁₁ is independently C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkoxy, OH, halogen, CN, NR_(n3)R_(n4), C₃-C₈ cycloalkyl, orheterocyclyl comprising one or two 4- or 6-membered rings and 1-4heteroatoms selected from N, O, and S, wherein the cycloalkyl orheterocyclyl is optionally substituted with one or more C₁-C₆ alkyl,halogen, or C(O)—(C₂-C₄ alkenyl);

each R_(n1) and each R_(n2) are independently H or C₁-C₄ alkyl, orR_(n1) and R_(n2), together with the nitrogen atom to which they arebonded, form a 4- to 7-membered heterocyclyl ring comprising 1 to 3heteroatoms selected from N, O, and S, wherein the heterocyclyl isoptionally substituted with one or more C₁-C₆ alkyl;

each R_(n3) and each R_(n4) are independently H or C₁-C₄ alkyl;

W is NR₈C(O)R₉, C(O)R₉, or is of formula:

L₃ is a bond or an optionally substituted C₁-C₄ hydrocarbon chain,optionally wherein one or more carbon units of the hydrocarbon chain areindependently replaced with —C═O—, —O—, —S—, —NR_(L3a)—,—NR_(L3a)C(═O)—, —C(═O)NR_(L3a)—, —SC(═O)—, —C(═O)S—, —OC(═O)—,—C(═O)O—, —NR_(L3a)C(═S)—, —C(═S)NR_(L3a)—, trans-CR_(L3b)═CR_(L3b)—,cis-CR_(L3b)═CR_(L3b)—, —C≡C—, —S(═O)—, —S(═O)O—, —OS(═O)—,—S(═O)NR_(L3a)—, —NR_(L3a)S(═O)—, —S(═O)₂—, —S(═O)₂O—, —OS(═O)₂—,—S(═O)₂NR_(L3a)—, or —NR_(L3a)S(═O)₂—;

R_(L3a) is H, optionally substituted C₁-C₆ alkyl, or a nitrogenprotecting group;

each R_(L3b) is independently H, halogen, optionally substituted C₁-C₆alkyl, optionally substituted C₂-C₆ alkenyl, optionally substitutedC₂-C₆ alkyl, optionally substituted C₃-C₈ cycloalkyl, optionallysubstituted heterocyclyl comprising one or two 5- or 6-membered ringsand 1-4 heteroatoms selected from N, O, and S, optionally substitutedC₆-C₁₀ aryl, or optionally substituted heteroaryl comprising one or two5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, ortwo R_(L3b) groups are joined to form an optionally substituted C₃-C₈carbocycle or optionally substituted 4- to 7-membered heterocyclyl ringcomprising 1 to 3 heteroatoms selected from N, O, and S:

L₄ is a bond or an optionally substituted C₁-C₆ hydrocarbon chain:

each of R_(E1), R_(E2), and R_(E3) is independently H, halogen,optionally substituted C₁-C₆ alkyl, optionally substituted C₂-C₆alkenyl, optionally substituted C₂-C₆ alkynyl, optionally substitutedC₃-C₈ cycloalkyl, optionally substituted heterocyclyl comprising one ortwo 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, andS, optionally substituted C₆-C₁₀ aryl, or optionally substitutedheteroaryl comprising one or two 5- or 6-membered rings and 1-4heteroatoms selected from N, O, and S, CN, CH₂OR_(EE), CH₂N(R_(EE))₂,CH₂SR_(EE), OR_(EE), N(R_(EE))₂, Si(R_(EE))₃, or SR_(EE), or R_(E1) andR_(E3), or R_(E2) and R_(E3), or R_(E1) and R_(E2) are joined to form anoptionally substituted C₃-C₈ carbocycle or optionally substituted 4- to7-membered heterocyclyl ring comprising 1 to 3 heteroatoms selected fromN, O, and S;

each R_(EE) is independently H, optionally substituted C₁-C₆ alkyl,optionally substituted C₁-C₆ alkoxy, optionally substituted C₂-C₆alkenyl, optionally substituted C₂-C₆ alkynyl, optionally substitutedC₃-C₈ cycloalkyl, optionally substituted heterocyclyl comprising one ortwo 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, andS, optionally substituted C₆-C₁₀ aryl, or optionally substitutedheteroaryl comprising one or two 5- or 6-membered rings and 1-4heteroatoms selected from N, O, and S, or two R_(EE) groups are joinedto form an optionally substituted 4- to 7-membered heterocyclyl ringcomprising 1 to 3 heteroatoms selected from N, O, and S;

R_(E5) is halogen;

R_(E6) is H, optionally substituted C₁-C₆ alkyl, or a nitrogenprotecting group;

each Y is independently O, S, or NR_(E7);

R_(E7) is H, optionally substituted C₁-C₆ alkyl, or a nitrogenprotecting group;

a is 1 or 2; and

each z is independently 0, 1, 2, 3, 4, 5, or 6.

In one embodiment, the compound is of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

R₁ is C₃-C₈ cycloalkyl, heterocyclyl comprising one or two 5- or6-membered rings and 1-4 heteroatoms selected from N, O, and S, phenyl,or heteroaryl comprising one or two 5- or 6-membered rings and 1-4heteroatoms selected from N, O, and S, wherein the cycloalkyl,heterocyclyl, phenyl, or heteroaryl is optionally substituted with oneor more R_(a1); and R₂ is Q-R₂′, wherein Q is (CH₂)₀₋₃ and R₂′ is C₃-C₈cycloalkyl, heterocyclyl comprising one 4- to 7-membered ring and 1-3heteroatoms selected from N, O, and S, phenyl, or heteroaryl comprisingone 5- or 6-membered ring and 1-3 heteroatoms selected from N, O, and S,wherein the cycloalkyl, heterocyclyl, phenyl, or heteroaryl issubstituted with one or more R_(b1), provided that when Q is (CH₂)₀, R₂′is pyrrolidinyl, and R₃ is phenyl or phenyl substituted with halogen,then R₁, is not substituted phenyl; or

R₁ is phenyl or heteroaryl comprising one 5- or 6-membered ring and 1-3heteroatoms selected from N, O, and S, wherein the phenyl or heteroarylis substituted with one or more R_(a2); and R₂ is C₁-C₄ alkyl or C₃-C₆cycloalkyl, wherein the alkyl or cycloalkyl is optionally substitutedwith one or more R_(b2);

R₃ is C₆-C₁₀ aryl or heteroaryl comprising one or two 5- or 6-memberedrings and 1-4 heteroatoms selected from N, O, and S, wherein the aryl orheteroaryl is optionally substituted with one or more R₇;

R₄, R₅, and R₆ are each independently H or C₁-C₄ alkyl;

each R₇ is independently C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkoxy, OH, halogen, CN, or NR_(n3)R_(n4);

each R_(a1) is independently C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkoxy, OH, halogen, NR_(n3)R_(n4), O—(CH₂)₁₋₄—NR_(n1)R_(n2),NR_(n1)—(CH₂)₁₋₄—NR_(n1)R_(n2), C₃-C₈ cycloalkyl, heterocyclylcomprising one or two 4- to 6-membered rings and 1-4 heteroatomsselected from N, O, and S, phenyl, or heteroaryl comprising one or two5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S,wherein the cycloalkyl, heterocyclyl, phenyl, or heteroaryl isoptionally substituted with one or more R₁₁;

each R_(b1) is independently W, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy, C₁-C₆ haloalkoxy, OH, halogen, or NR_(n3)R_(n4), wherein atleast one R_(b1) is W, or when the at least one R_(b1) is bonded to anitrogen atom in a heterocyclyl ring comprising at least one nitrogenatom, R_(b1) is C(O)R₉;

each R_(a2) is independently W, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy, C₁-C₆ haloalkoxy, OH, halogen, NR_(n3)R_(n4),O—(CH₂)₁₋₄—NR_(n1)R_(n2), NR_(n1)—(CH₂)₁₋₄—NR_(n1)R_(n2), C₃-C₈cycloalkyl, heterocyclyl comprising one or two 4- to 6-membered ringsand 1-4 heteroatoms selected from N, O, and S, phenyl, or heteroarylcomprising one or two 5- or 6-membered rings and 1-4 heteroatomsselected from N, O, and S, wherein the cycloalkyl, heterocyclyl, phenyl,or heteroaryl is optionally substituted with one or more R₁₁, wherein atleast one R_(a2) is W;

each R_(b2) is independently C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkoxy, OH, halogen, or NR_(n3)R_(n4);

each R₈ is independently H or C₁-C₄ alkyl;

each R₉ is independently C₂-C₄ alkenyl optionally substituted with oneor more R₁₀;

each R₁₀ is independently NR_(n3)R_(n4);

each R₁₁ is independently C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkoxy, OH, halogen, NR_(n3)R_(n4), C₃-C₈ cycloalkyl, orheterocyclyl comprising one or two 5- or 6-membered rings and 1-4heteroatoms selected from N, O, and S, wherein the cycloalkyl orheterocyclyl is optionally substituted with one or more C₁-C₆ alkyl:

each R_(n1) and each R_(n2) are independently H or C₁-C₄ alkyl, orR_(n1) and R_(n2), together with the nitrogen atom to which they arebonded, form a 4- to 7-membered heterocyclyl ring comprising 1 to 3heteroatoms selected from N, O, and S, wherein the heterocyclyl isoptionally substituted with one or more C₁-C₆ alkyl;

each R₃ and each R_(n4) are independently H or C₁-C₄ alkyl;

W is NR₈C(O)R₉, C(O)R₉, or is of formula:

L₃ is a bond or an optionally substituted C₁-C₄ hydrocarbon chain,optionally wherein one or more carbon units of the hydrocarbon chain areindependently replaced with —C═O—, —O—, —S—, —NR_(L3a)—,—NR_(L3a)C(═O)—, —C(O)NR_(L3a)—, —SC(═O)—, —C(═O)S—, —OC(═O)—, —C(═O)O—,—NR_(L3a)C(═S)—, —C(═S)NR_(L3a)—, trans-CR_(L3b)═CR_(L3b)—,cis-CR_(L3b)═CR_(L3b)—, —C≡C—, —S(═O)—, —S(═O)O—, —OS(═O)—,—S(═O)NR_(L3a)—, —NR_(L3a)S(═O)—, —S(═O)₂—, —S(═O)₂O—, —OS(═O)₂—,—S(═O)₂NR_(L3a)—, or —NR_(L3a)S(═O)₂—;

R_(L3a) is H, optionally substituted C₁-C₆ alkyl, or a nitrogenprotecting group;

each R_(L3b) is independently H, halogen, optionally substituted C₁-C₆alkyl, optionally substituted C₂-C₆ alkenyl, optionally substitutedC₂-C₆ alkynyl, optionally substituted C₃-C₈ cycloalkyl, optionallysubstituted heterocyclyl comprising one or two 5- or 6-membered ringsand 1-4 heteroatoms selected from N, O, and S, optionally substitutedC₆-C₁₀ aryl, or optionally substituted heteroaryl comprising one or two5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, ortwo R_(L3b) groups are joined to form an optionally substituted C₃-C₈carbocycle or optionally substituted 4- to 7-membered heterocyclyl ringcomprising 1 to 3 heteroatoms selected from N, O, and S;

L₄ is a bond or an optionally substituted C₁-C₆ hydrocarbon chain;

each of R_(E1), R_(E2), and R_(E3) is independently H, halogen,optionally substituted C₁-C₆ alkyl, optionally substituted C₂-C₆alkenyl, optionally substituted C₂-C₆ alkynyl, optionally substitutedC₃-C₈ cycloalkyl, optionally substituted heterocyclyl comprising one ortwo 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, andS, optionally substituted C₆-C₁₀ aryl, or optionally substitutedheteroaryl comprising one or two 5- or 6-membered rings and 1-4heteroatoms selected from N, O, and S, CN, CH₂OR_(EE), CH₂N(R_(EE))₂,CH₂SR_(EE), OR_(EE), N(R_(EE))₂, Si(R_(EE))₃, or SR_(EE), or R_(E1) andR_(E3), or R_(E2) and R_(E3), or R_(E1) and R_(E2) are joined to form anoptionally substituted C₃-C₈ carbocycle or optionally substituted 4- to7-membered heterocyclyl ring comprising 1 to 3 heteroatoms selected fromN, O, and S;

each R_(EE) is independently H, optionally substituted C₁-C₆ alkyl,optionally substituted C₁-C₆ alkoxy, optionally substituted C₂-C₆alkenyl, optionally substituted C₂-C₆ alkynyl, optionally substitutedC₃-C₈ cycloalkyl, optionally substituted heterocyclyl comprising one ortwo 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, andS, optionally substituted C₆-C₁₀ aryl, or optionally substitutedheteroaryl comprising one or two 5- or 6-membered rings and 1-4heteroatoms selected from N, O, and S, or two R_(EE) groups are joinedto form an optionally substituted 4- to 7-membered heterocyclyl ringcomprising 1 to 3 heteroatoms selected from N, O, and S:

R_(E5) is halogen;

R_(E6) is H, optionally substituted C₁-C₆ alkyl, or a nitrogenprotecting group;

each Y is independently O, S, or NR_(E7);

R_(E7) is H, optionally substituted C₁-C₆ alkyl, or a nitrogenprotecting group;

a is 1 or 2; and

each z is independently 0, 1, 2, 3, 4, 5, or 6.

For any of the Formulae described herein, where applicable:

(I1) In one embodiment, R₂ is Q-R₂′; and R₁ is C₃-C₈ cycloalkyl selectedfrom cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, andcyclooctyl, each of which is optionally substituted with one or moreR_(a1).

(I2) In one embodiment, R₂ is Q-R₂′; and R₁ is heterocyclyl comprisingone or two 5- or 6-membered rings and 1-4 heteroatoms selected from N,O, and S optionally substituted with one or more R_(a1). In a furtherembodiment, R₁ is heterocyclyl comprising one 5- or 6-membered ring and1-4 heteroatoms selected from N, O, and S (e.g., pyrrolidinyl,tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl,oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl,triazolidinyl, oxadiazolidinyl, isoxadiazolidinyl, thiadiazolidinyl,isothiadiazolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl,hexahydropyridazinyl, hexahydropyrimidinyl, morpholinyl, triazinanyl,etc.) optionally substituted with one or more R_(a1). In a furtherembodiment, R₁ is piperidinyl or piperazinyl optionally substituted withone or more R_(a1).

(I3) In one embodiment, R₂ is Q-R₂′; and R₁ is phenyl or heteroarylcomprising one or two 5- or 6-membered rings and 1-4 heteroatomsselected from N, O, and S, each optionally substituted with one or moreR_(a1).

(I4) In one embodiment, R₂ is Q-R₂′; and R₁ is phenyl optionallysubstituted with one or more R_(a1).

(I5) In one embodiment, R₂ is Q-R₂′; and R₁ is heteroaryl comprising oneor two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O,and S optionally substituted with one or more R_(a1). In a furtherembodiment, R₁ is heteroaryl comprising one 5- or 6-membered ring and1-4 heteroatoms selected from N, O, and S (e.g., pyrrolyl, furanyl,thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl,pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, thiopyranyl,diazinyl, thiazinyl, dioxinyl, triazinyl, etc.) optionally substitutedwith one or more R_(a1). In a further embodiment, R₁ is heteroarylcomprising one 5-membered ring and 1-4 heteroatoms selected from N, O,and S (e.g., pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl,oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl,thiadiazolyl, tetrazolyl, etc.) optionally substituted with one or moreR_(a1). In a further embodiment, R₁ is pyrazolyl or pyridinyl optionallysubstituted with one or more R_(a1). In a further embodiment, R₁ ispyrazolyl optionally substituted with one or more R_(a1).

(I6) In one embodiment, R₂ is Q-R₂′; and R₁ is H.

(I7) In one embodiment, R₂ is Q-R₂′; and R₁ is C₁-C₄ alkyl. In oneembodiment, R₁ is methyl.

(I8) In one embodiment, R₂ is Q-R₂′; and R₁ is C(O)—(C₁-C₄ alkyl). Inone embodiment, R₁ is C(O)CH₃.

(II1) In one embodiment, in each of (I1)-(I8), R₂′ is C₃-C₈ cycloalkylselected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, and cyclooctyl, each of which is substituted with one ormore R_(b1). In a further embodiment, R₂′ is cyclobutyl, cyclopentyl, orcyclohexyl, each of which is substituted with one or more R_(b1).

(II2) In one embodiment, in each of (I1)-(I8), R₂′ is heterocyclylcomprising one 4- to 7-membered ring and 1-3 heteroatoms selected fromN, O, and S (e.g., azetidinyl, oxetanyl, oxazetidinyl, diazetidinyl,pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl,imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl,isothiazolidinyl, triazolidinyl, oxadiazolidinyl, isoxadiazolidinyl,thiadiazolidinyl, isothiadiazolidinyl, piperidinyl, piperazinyl,tetrahydropyranyl, hexahydropyridazinyl, hexahydropyrimidinyl,morpholinyl, triazinanyl, azepanyl, oxazepanyl, diazepanyl, etc.)substituted with one or more R_(b1). In a further embodiment, R₂′ ispyrrolidinyl, piperidinyl, piperazinyl, or azepanyl, each of which issubstituted with one or more R_(b1).

(II3) In one embodiment, in each of (I1)-(I8), R₂′ is phenyl substitutedwith one or more R_(b1).

(II4) In one embodiment, in each of (I1)-(I8), R₂′ is heteroarylcomprising one 5- or 6-membered ring and 1-3 heteroatoms selected fromN, O, and S (e.g., pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl,oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl,thiadiazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, pyranyl, thiopyranyl, diazinyl, thiazinyl, dioxinyl,triazinyl, etc.) substituted with one or more R_(b1). In a furtherembodiment, R₁ is pyridinyl substituted with one or more R_(b1).

(III1) In one embodiment, in each of (II1)-(II4), Q is (CH₂)₀.

(III2) In one embodiment, in each of (II1)-(II4), Q is (CH₂)₁₋₃. In afurther embodiment, Q is (CH₂)₁.

(III3) In one embodiment, R₁ and R₂′ are each as described herein, forexample, where applicable, in any of (I1)-(I8) and (II3) and (II4), Q is(CH₂)₀.

(III4) In one embodiment, R₁ and R₂′ are each as described herein, forexample, where applicable, in any of (I1)-(I8) and (II1) and (II2), Q is(CH₂)₀₋₃. In a further embodiment, Q is (CH₂)₀. In a further embodiment,Q is (CH₂)₁.

(IV1) In one embodiment, at least one R_(a1) is C₁-C₆ straight-chain orC₃-C₆ branched alkyl, including methyl, ethyl, n-propyl, i-propyl,n-butyl, i-butyl, s-butyl, t-butyl, pentyl, and hexyl. In a furtherembodiment, at least one R_(a1) is C₁-C₄ alkyl selected from methyl,ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, and t-butyl. In afurther embodiment, at least one R_(a1) is methyl.

(IV2) In one embodiment, at least one R_(a1) is C₁-C₆ straight-chain orC₃-C₆ branched haloalkyl, including methyl, ethyl, n-propyl, i-propyl,n-butyl, i-butyl, s-butyl, t-butyl, pentyl, and hexyl, each of which issubstituted with one or more halogen (e.g., F, Cl, Br, or I). In afurther embodiment, at least one R_(a1) is C₁-C₄ haloalkyl selected frommethyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, andt-butyl, each of which is substituted with one or more halogen (e.g., F,Cl, Br, or I). In a further embodiment, at least one R_(a1) is CH₂F,CHF₂, or CF₃.

(IV3) In one embodiment, at least one R_(a1) is C₁-C₆ straight-chain orC₃-C₆ branched alkoxy, including methoxy, ethoxy, n-propoxy, i-propoxy,n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, and hexyloxy. In afurther embodiment, at least one R_(a1) is C₁-C₄ alkoxy selected frommethoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, andt-butoxy. In a further embodiment, at least one R_(a1) is methoxy orethoxy.

(IV4) In one embodiment, at least one R_(a1) is C₁-C₆ straight-chain orC₃-C₆ branched haloalkoxy, including methoxy, ethoxy, n-propoxy,i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, andhexyloxy, each of which is substituted with one or more halogen (e.g.,F, Cl, Br, or I). In a further embodiment, at least one R_(a1) is C₁-C₄haloalkoxy selected methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy,i-butoxy, s-butoxy, and t-butoxy, each of which is substituted with oneor more halogen (e.g., F, Cl, Br, or I). In a further embodiment, atleast one R_(a1) is OCH₂F, OCHF₂, or OCF₃.

(IV5) In one embodiment, at least one R_(a1) is OH.

(IV6) In one embodiment, at least one R_(a1) is halogen (e.g., F, Cl,Br, or I). In a further embodiment, at least one R_(a1) is F or Cl. In afurther embodiment, at least one R_(a1) is F.

(IV7) In one embodiment, at least one R_(a1) is NH₂. In one embodiment,at least one R_(a1) is NR_(n3)R_(n4), wherein R_(n3) and R_(n4) are eachindependently C₁-C₄ alkyl selected from methyl, ethyl, n-propyl,i-propyl, n-butyl, i-butyl, s-butyl, and t-butyl.

(IV8) In one embodiment, at least one R_(a1) is O—(CH₂)₁₋₄—NR_(n1)R_(n2)or NR_(n1)—(CH₂)₁₋₄—NR_(n1)R_(n2), wherein each R_(n1) and R_(n2) are H.In one embodiment, at least one R_(a1) is O—(CH₂)₁₋₄—NR_(n1)R_(n2) orNR_(n1)—(CH₂)₁₋₄—NR_(n1)R_(n2), wherein each R_(n1) is independently Hor C₁-C₄ alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl,i-butyl, s-butyl, or t-butyl), and R_(a2) is C₁-C₄ alkyl (e.g., methyl,ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl). Inone embodiment, at least one R_(a1) is O—(CH₂)₄—NR_(n1)R_(n2) orNH—(CH₂)₁₋₄—NR_(n1)R_(n2), wherein R_(n1) and R_(n2) are eachindependently C₁-C₄ alkyl (e.g., methyl, ethyl, n-propyl, i-propyl,n-butyl, i-butyl, s-butyl, or t-butyl).

(IV9) In one embodiment, at least one R_(a1) is O—(CH₂)₁₋₄—NR_(n1)R_(n2)or NH—(CH₂)₁₋₄—NR_(n1)R_(n2), wherein R_(n1) and R_(n2), together withthe nitrogen atom to which they are bonded, form a 4- to 7-memberedheterocyclyl ring comprising 1 to 3 heteroatoms selected from N, O, andS (e.g., azetidinyl, oxetanyl, oxazetidinyl, diazetidinyl, pyrrolidinyl,tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl,oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl,triazolidinyl, oxadiazolidinyl, isoxadiazolidinyl, thiadiazolidinyl,isothiadiazolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl,hexahydropyridazinyl, hexahydropyrimidinyl, morpholinyl, triazinanyl,azepanyl, oxazepanyl, diazepanyl, etc.) optionally substituted with oneor more C₁-C₆ alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl,i-butyl, s-butyl, t-butyl, pentyl, or hexyl). In a further embodiment,R_(n1) and R_(n2), together with the nitrogen atom to which they arebonded, form a 5- or 6-membered heterocyclyl ring comprising 1 to 3heteroatoms selected from N, O, and S (e.g., pyrrolidinyl,tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl,oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl,triazolidinyl, oxadiazolidinyl, isoxadiazolidinyl, thiadiazolidinyl,isothiadiazolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl,hexahydropyridazinyl, hexahydropyrimidinyl, morpholinyl, triazinanyl,etc.) optionally substituted with one or more C₁-C₆ alkyl (e.g., methyl,ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl,or hexyl). In a further embodiment, R_(n1) and R_(n2), together with thenitrogen atom to which they are bonded, form a pyrrolidinyl orpiperidinyl ring optionally substituted with one or more C₁-C₆ alkyl(e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl,t-butyl, pentyl, or hexyl).

(IV10) In one embodiment, in (IV8) or (IV9), at least one R_(a1) isO—(CH₂)₁₋₄—NR_(n1)R_(n2). In a further embodiment, at least one R_(a1)is O—(CH₂)₁—NR_(n1)R_(n2). In another further embodiment, at least oneR_(a1) is O—(CH₂)₂—NR_(n1)R_(n2).

(IV11) In one embodiment, in (IV8) or (IV9), at least one R_(a1) isNR_(n1)—(CH₂)₁₋₄—NR_(n1)R_(n2). In a further embodiment, at least oneR_(a1) is NR_(n1)—(CH₂)₁—NR_(n1)R_(n2). In another further embodiment,at least one R_(a1) is NR_(n1)—(CH₂)₂—NR_(n1)R_(n2).

(IV12) In one embodiment, at least one R_(a1) is C₃-C₈ cycloalkylselected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, and cyclooctyl, each of which is optionally substitutedwith one or more R₁₁.

(IV13) In one embodiment, at least one R_(a1) is heterocyclyl comprisingone or two 4- to 6-membered rings and 1-4 heteroatoms selected from N,O, and S optionally substituted with one or more R₁₁. In a furtherembodiment, at least one R_(a1) is heterocyclyl comprising one 4- to6-membered ring and 1-4 heteroatoms selected from N, O, and S (e.g.,azetidinyl, oxetanyl, oxazetidinyl, diazetidinyl, pyrrolidinyl,tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl,oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl,triazolidinyl, oxadiazolidinyl, isoxadiazolidinyl, thiadiazolidinyl,isothiadiazolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl,hexahydropyridazinyl, hexahydropyrimidinyl, morpholinyl, triazinanyl,etc.) optionally substituted with one or more R₁₁. In a furtherembodiment, at least one R_(a1) is azetidinyl, pyrrolidinyl,piperidinyl, or piperazinyl optionally substituted with one or more R₁₁.

(IV14) In one embodiment, at least one R_(a1) is phenyl optionallysubstituted with one or more R₁₁.

(IV15) In one embodiment, at least one R_(a1) is heteroaryl comprisingone or two 5- or 6-membered rings and 1-4 heteroatoms selected from N,O, and S optionally substituted with one or more R₁₁. In a furtherembodiment, at least one R_(a1) is heteroaryl comprising one 5- or6-membered ring and 1-4 heteroatoms selected from N, O, and S (e.g.,pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl,thiadiazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, pyranyl, thiopyranyl, diazinyl, thiazinyl, dioxinyl,triazinyl, etc.) optionally substituted with one or more R₁₁. In afurther embodiment, at least one R_(a1) is heteroaryl comprising one5-membered ring and 1-4 heteroatoms selected from N, O, and S (e.g.,pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl,thiadiazolyl, tetrazolyl, etc.) optionally substituted with one or moreR₁₁.

(IV16) In one embodiment, at least one R_(a1) is C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, OH, halogen, NR_(n3)R_(n4),O—(CH₂)₁₋₄—NR_(n1)R_(n2), NR_(n1)—(CH₂)₁₋₄—NR_(n1)R_(n2), orheterocyclyl comprising one or two 4- to 6-membered rings and 1-4heteroatoms selected from N, O, and S, wherein the heterocyclyl isoptionally substituted with one or more R₁₁, wherein the C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halogen, NR_(n3)R_(n4),O—(CH₂)₁₋₄—NR_(n1)R_(n2), NR_(n1)—(CH₂)₁₋₄—NR_(n1)R_(n2), andheterocyclyl are each as described herein, for example, whereapplicable, in any of (IV1)-(IV15).

(IV17) In one embodiment, at least one R_(a1) is C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, OH, halogen, NR_(n3)R_(n4),O—(CH₂)₁₋₄—NR_(n1)R_(n2), or NR_(n1)—(CH₂)₁₋₄—NR_(n1)R_(n2), wherein theC₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halogen,NR_(n3)R_(n4), O—(CH₂)₁₋₄—NR_(n1)R_(n2), andNR_(n1)—(CH₂)₁₋₄—NR_(n1)R_(n2) are each as described herein, forexample, where applicable, in any of (IV1)-(IV15).

(IV18) In one embodiment, at least one R_(a1) is C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, OH, halogen, orNR_(n3)R_(n4), wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl. C₁-C₆ alkoxy,C₁-C₆ haloalkoxy, halogen, and NR_(n3)R_(n4) are each as describedherein, for example, where applicable, in any of (IV1)-(IV15).

(IV19) In one embodiment, at least one R_(a1) is C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, OH, halogen, or heterocyclylcomprising one or two 4- to 6-membered rings and 1-4 heteroatomsselected from N, O, and S, wherein the heterocyclyl is optionallysubstituted with one or more R₁₁, wherein the C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halogen, and heterocyclyl areeach as described herein, for example, where applicable, in any of(IV1)-(IV15).

(IV20) In one embodiment, at least one R_(a1) is C₃-C₈ cycloalkyl,heterocyclyl comprising one or two 4- to 6-membered rings and 1-4heteroatoms selected from N, O, and S, phenyl, or heteroaryl comprisingone or two 5- or 6-membered rings and 1-4 heteroatoms selected from N,O, and S, wherein the cycloalkyl, heterocyclyl, phenyl, or heteroaryl isoptionally substituted with one or more R₁₁, wherein the cycloalkyl,heterocyclyl, phenyl, and heteroaryl are each as described herein, forexample, where applicable, in any of (IV1)-(IV 15).

(IV21) In one embodiment, at least one R_(a1) is C₃-C₈ cycloalkyl orheterocyclyl comprising one or two 4- to 6-membered rings and 1-4heteroatoms selected from N, O, and S, wherein the cycloalkyl andheterocyclyl are each optionally substituted with one or more R₁₁,wherein the cycloalkyl and heterocyclyl are each as described herein,for example, where applicable, in any of (IV1)-(IV15).

(IV22) In one embodiment, at least one R_(a1) is NH—C(O)—(C₂-C₄alkenyl). In one embodiment, at least one R_(a1) is NH—C(O)—CH₂CH₃.

(IV23) In one embodiment, at least one R_(a1) is C₁-C₆ alkyl optionallysubstituted with one or more R₁₁.

(V1) In one embodiment, R₂′ is substituted with one R_(b1), and the oneR_(b1) is NR₈C(O)R₉.

(V2) In one embodiment, R₂′ is substituted with two or more Rb*, oneR_(b1) is NR₈C(O)R₉, and at least one R_(b1) is C₁-C₆ straight-chain orC₃-C₆ branched alkyl, including methyl, ethyl, n-propyl, i-propyl,n-butyl, i-butyl, s-butyl, t-butyl, pentyl, and hexyl. In a furtherembodiment, at least one R_(b1) is C₁-C₄ alkyl selected from methyl,ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, and t-butyl.

(V3) In one embodiment, R₂′ is substituted with two or more R_(b1), oneR_(b1) is NR₈C(O)R₉, and at least one R_(b1) is C₁-C₆ straight-chain orC₃-C₆ branched haloalkyl, including methyl, ethyl, n-propyl, i-propyl,n-butyl, i-butyl, s-butyl, t-butyl, pentyl, and hexyl, each of which issubstituted with one or more halogen (e.g., F, Cl, Br, or I). In afurther embodiment, at least one R_(b1) is C₁-C₄ haloalkyl selected frommethyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, andt-butyl, each of which is substituted with one or more halogen (e.g., F,Cl, Br, or I).

(V4) In one embodiment, R₂′ is substituted with two or more R_(b1), oneR_(b1) is NR₈C(O)R₉, and at least one R_(b1) is C₁-C₆ straight-chain orC₃-C₆ branched alkoxy, including methoxy, ethoxy, n-propoxy, i-propoxy,n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, and hexyloxy. In afurther embodiment, at least one R_(b1) is C₁-C₄ alkoxy selected frommethoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, andt-butoxy.

(V5) In one embodiment, R₂′ is substituted with two or more R_(b1), oneR_(b1) is NR₈C(O)R₉, and at least one R_(b1) is C₁-C₆ straight-chain orC₃-C₆ branched haloalkoxy, including methoxy, ethoxy, n-propoxy,i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, andhexyloxy, each of which is substituted with one or more halogen (e.g.,F, Cl, Br, or I). In a further embodiment, at least one R_(b1) is C₁-C₄haloalkoxy selected methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy,i-butoxy, s-butoxy, and t-butoxy, each of which is substituted with oneor more halogen (e.g., F, Cl, Br, or I).

(V6) In one embodiment, R₂′ is substituted with two or more R_(b1), oneR_(b1) is NR₈C(O)R₉, and at least one R_(b1) is OH.

(V7) In one embodiment, R₂′ is substituted with two or more R_(b1), oneR_(b1) is NR₈C(O)R₉, and at least one R_(b1) is halogen (e.g., F, Cl,Br, or I).

(V8) In one embodiment, R₂′ is substituted with two or more R_(b1), oneR_(b1) is NR₈C(O)R₉, and at least one R_(b1) is NH₂. In one embodiment,at least one R_(b1) is NR_(n3)R_(n4), wherein R_(n3) and R_(n4) are eachindependently C₁-C₄ alkyl selected from methyl, ethyl, n-propyl,i-propyl, n-butyl, i-butyl, s-butyl, and t-butyl.

(VI1) In one embodiment, R₁ is phenyl substituted with one or moreR_(a2); and R₂ is C₁-C₄ alkyl or C₃-C₆ cycloalkyl, wherein the alkyl orcycloalkyl is optionally substituted with one or more R_(b2).

(VI2) In one embodiment, R₁ is heteroaryl comprising one 5- or6-membered ring and 1-3 heteroatoms selected from N, O, and Ssubstituted with one or more R_(a2); and R₂ is C₁-C₄ alkyl or C₃-C₆cycloalkyl, wherein the alkyl or cycloalkyl is optionally substitutedwith one or more R_(b2). In a further embodiment, R₁ is heteroarylcomprising one 5- or 6-membered ring and 1-3 heteroatoms selected fromN, O, and S (e.g., pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl,oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl,thiadiazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, pyranyl, thiopyranyl, diazinyl, thiazinyl, dioxinyl,triazinyl, etc.) substituted with one or more R_(a2). In a furtherembodiment, R₁ is pyrazolyl or pyridinyl optionally substituted with oneor more R_(a2). In a further embodiment, R₁ is pyridinyl substitutedwith one or more R_(a2).

(VII1) In one embodiment, in (VI1) or (VI2), R₂ is C₁-C₁ alkyl selectedfrom methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, andt-butyl, each of which is optionally substituted with one or moreR_(b2). In a further embodiment, R₂ is methyl optionally substitutedwith one or more R_(b2).

(VII2) In one embodiment, in (VI1) or (VI2), R₂ is C₃-C₈ cycloalkylselected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, and cyclooctyl, each of which is optionally substitutedwith one or more R_(b2). In a further embodiment, R₂ is cyclobutyl,cyclopentyl, or cyclohexyl, each of which is optionally substituted withone or more R_(b2).

(VIII1) In one embodiment, R₁ is substituted with one R_(a2), and theone R_(a2) is NR₈C(O)R₉.

(VIII2) In one embodiment, R₁ is substituted with two or more R_(a2),one R_(a2) is NR₈C(O)R₉, and at least one R_(a2) is C₁-C₆ straight-chainor C₃-C₆ branched alkyl, including methyl, ethyl, n-propyl, i-propyl,n-butyl, i-butyl, s-butyl, t-butyl, pentyl, and hexyl. In a furtherembodiment, at least one R_(a2) is C₁-C₄ alkyl selected from methyl,ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, and t-butyl. In afurther embodiment, at least one R_(a2) is methyl.

(VIII3) In one embodiment, R₁ is substituted with two or more R_(a2),one R_(a2) is NR₈C(O)R₉, and at least one R_(a2) is C₁-C₆ straight-chainor C₃-C₆ branched haloalkyl, including methyl, ethyl, n-propyl,i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, and hexyl, each ofwhich is substituted with one or more halogen (e.g., F, Cl, Br, or I).In a further embodiment, at least one R_(a2) is C₁-C₄ haloalkyl selectedfrom methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, andt-butyl, each of which is substituted with one or more halogen (e.g., F,Cl, Br, or I). In a further embodiment, at least one R_(a2) is CH₂F,CHF₂, or CF₃.

(VIII4) In one embodiment, R₁ is substituted with two or more R_(a2),one R_(a2) is NR₈C(O)R₉, and at least one R_(a2) is C₁-C₆ straight-chainor C₃-C₆ branched alkoxy, including methoxy, ethoxy, n-propoxy,i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, andhexyloxy. In a further embodiment, at least one R_(a2) is C₁-C₄ alkoxyselected from methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy,s-butoxy, and t-butoxy. In a further embodiment, at least one R_(a2) ismethoxy or ethoxy.

(VIII5) In one embodiment, R₁ is substituted with two or more R_(a2),one R_(a2) is NR₈C(O)R₉, and at least one R_(a2) is C₁-C₆ straight-chainor C₃-C₆ branched haloalkoxy, including methoxy, ethoxy, n-propoxy,i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, andhexyloxy, each of which is substituted with one or more halogen (e.g.,F, Cl, Br, or I). In a further embodiment, at least one R_(a2) is C₁-C₄haloalkoxy selected methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy,i-butoxy, s-butoxy, and t-butoxy, each of which is substituted with oneor more halogen (e.g., F, Cl, Br, or I). In a further embodiment, atleast one R_(a2) is OCH₂F, OCHF₂, or OCF₃.

(VIII6) In one embodiment, R₁ is substituted with two or more R_(a2),one R_(a2) is NR₈C(O)R₉, and at least one R_(a2) is OH.

(VIII7) In one embodiment, R₁ is substituted with two or more R_(a2),one R_(a2) is NR₈C(O)R₉, and at least one R_(a2) is halogen (e.g., F,Cl, Br, or I). In a further embodiment, at least one R_(a2) is F or Cl.In a further embodiment, at least one R_(a2) is F.

(VIII8) In one embodiment, R₁ is substituted with two or more R_(a2),one R_(a2) is NR₈C(O)R₉, and at least one R_(a2) is NH₂. In oneembodiment, at least one R_(a2) is NR_(n3)R_(n4), wherein R_(n3) andR_(n4) are each independently C₁-C₄ alkyl selected from methyl, ethyl,n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, and t-butyl.

(VIII9) In one embodiment, R₁ is substituted with two or more R_(a2),one R_(a2) is NR₈C(O)R₉, and at least one R_(a2) isO—(CH₂)₁₄—NR_(n1)R_(n2) or NR_(n1)—(CH₂)₁₋₄—NR_(n1)R_(n2), wherein eachR_(n1) and R_(n2) are H. In one embodiment, at least one R_(a2) isO—(CH₂)₁₋₄—NR_(n1)R_(n2) or NR_(n1)—(CH₂)₁₋₄—NR_(n1)R_(n2), wherein eachR_(n1) is independently H or C₁-C₄ alkyl (e.g., methyl, ethyl, n-propyl,i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl), and R_(n2) is C₁-C₄alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,s-butyl, or t-butyl). In one embodiment, at least one R_(a2) isO—(CH₂)₄—NR_(n1)R_(n2) or NH—(CH₂)₁₋₄—NR_(n1)R_(n2), wherein R_(n1) andR_(n2) are each independently C₁-C₄ alkyl (e.g., methyl, ethyl,n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl).

(VIII10) In one embodiment, R₁ is substituted with two or more R_(a2),one R_(a2) is NR₈C(O)R₉, and at least one R_(a2) isO—(CH₂)₁₋₄—NR_(n1)R_(n2) or NH—(CH₂)₁₋₄—NR_(n1)R_(n2), wherein R_(n1)and R_(n2), together with the nitrogen atom to which they are bonded,form a 4- to 7-membered heterocyclyl ring comprising 1 to 3 heteroatomsselected from N, O, and S (e.g., azetidinyl, oxetanyl, oxazetidinyl,diazetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl,pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl,thiazolidinyl, isothiazolidinyl, triazolidinyl, oxadiazolidinyl,isoxadiazolidinyl, thiadiazolidinyl, isothiadiazolidinyl, piperidinyl,piperazinyl, tetrahydropyranyl, hexahydropyridazinyl,hexahydropyrimidinyl, morpholinyl, triazinanyl, azepanyl, oxazepanyl,diazepanyl, etc.) optionally substituted with one or more C₁-C₆ alkyl(e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl,t-butyl, pentyl, or hexyl). In a further embodiment, R_(n1) and R_(n2),together with the nitrogen atom to which they are bonded, form a 5- or6-membered heterocyclyl ring comprising 1 to 3 heteroatoms selected fromN, O, and S (e.g., pyrrolidinyl, tetrahydrofuranyl,tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl,isoxazolidinyl, thiazolidinyl, isothiazolidinyl, triazolidinyl,oxadiazolidinyl, isoxadiazolidinyl, thiadiazolidinyl,isothiadiazolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl,hexahydropyridazinyl, hexahydropyrimidinyl, morpholinyl, triazinanyl,etc.) optionally substituted with one or more C₁-C₆ alkyl (e.g., methyl,ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl,or hexyl). In a further embodiment, R_(n1) and R_(n2), together with thenitrogen atom to which they are bonded, form a pyrrolidinyl orpiperidinyl ring optionally substituted with one or more C₁-C₆ alkyl(e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl,t-butyl, pentyl, or hexyl).

(VIII11) In one embodiment, in (VIII9) or (VIII10), R₁ is substitutedwith two or more R_(a2), one R_(a2) is NR₈C(O)R₉, and at least oneR_(a2) is O—(CH₂)₁₋₄—NR_(n1)R_(n2). In a further embodiment, at leastone R_(a2) is O—(CH₂)₁—NR_(n1)R_(n2). In another further embodiment, atleast one R_(a2) is O—(CH₂)₂—NR_(n1)R_(n2).

(VIII12) In one embodiment, in (VIII9) or (VIII10), R₁ is substitutedwith two or more R_(a2), one R_(a2) is NR₈C(O)R₉, and at least one R₂ isNR_(n1)—(CH₂)₁₋₄—NR_(n1)R_(n2). In a further embodiment, at least oneR_(a2) is NR_(n1)—(CH₂)₁—NR_(n1)R_(n2). In another further embodiment,at least one R_(a2) is NR_(n1)—(CH₂)₂—NR_(n1)R_(n2).

(VIII13) In one embodiment, R₁ is substituted with two or more R_(a2),one R_(a2) is NR₈C(O)R₉, and at least one R_(a2) is C₃-C₈ cycloalkylselected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, and cyclooctyl, each of which is optionally substitutedwith one or more R₁₁.

(VIII14) In one embodiment, R₁ is substituted with two or more R₂, oneR_(a2) is NR₈C(O)R₉, and at least one R_(a2) is heterocyclyl comprisingone or two 4- to 6-membered rings and 1-4 heteroatoms selected from N,O, and S optionally substituted with one or more R₁₁. In a furtherembodiment, at least one R_(a2) is heterocyclyl comprising one 4- to6-membered ring and 1-4 heteroatoms selected from N, O, and S (e.g.,azetidinyl, oxetanyl, oxazetidinyl, diazetidinyl, pyrrolidinyl,tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl,oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl,triazolidinyl, oxadiazolidinyl, isoxadiazolidinyl, thiadiazolidinyl,isothiadiazolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl,hexahydropyridazinyl, hexahydropyrimidinyl, morpholinyl, triazinanyl,etc.) optionally substituted with one or more R₁₁. In a furtherembodiment, at least one R_(a2) is azetidinyl, pyrrolidinyl,piperidinyl, or piperazinyl optionally substituted with one or more R₁₁.

(VIII5) In one embodiment, R₁ is substituted with two or more R_(a2),one R_(a2) is NR₈C(O)R₉, and at least one R_(a2) is phenyl optionallysubstituted with one or more R₁₁.

(VIII16) In one embodiment, R₁ is substituted with two or more R_(a2),one R_(a2) is NR₈C(O)R₉, and at least one R_(a2) is heteroarylcomprising one or two 5- or 6-membered rings and 1-4 heteroatomsselected from N, O, and S optionally substituted with one or more R₁₁.In a further embodiment, at least one R_(a2) is heteroaryl comprisingone 5- or 6-membered ring and 1-4 heteroatoms selected from N, O, and S(e.g., pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl,thiadiazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, pyranyl, thiopyranyl, diazinyl, thiazinyl, dioxinyl,triazinyl, etc.) optionally substituted with one or more R₁₁. In afurther embodiment, at least one R_(a2) is heteroaryl comprising one5-membered ring and 1-4 heteroatoms selected from N, O, and S (e.g.,pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl,thiadiazolyl, tetrazolyl, etc.) optionally substituted with one or moreR₁₁.

(VIII17) In one embodiment, R₁ is phenyl substituted with one or moreR_(a2); and R₂ is H.

(VIII18) In one embodiment, at least one R_(a2) is C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, OH, halogen, NR_(n3)R_(n4),O—(CH₂)₁₋₄—NR_(n1)R_(n2), NR_(n1)—(CH₂)₁₋₄—NR_(n1)R_(n2), orheterocyclyl comprising one or two 4- to 6-membered rings and 1-4heteroatoms selected from N, O, and S, wherein the heterocyclyl isoptionally substituted with one or more R₁₁, wherein the C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halogen, NR_(n3)R_(n4),O—(CH₂)₁₋₄—NR_(n1)R_(n2), NR_(n1)—(CH₂)₁₋₄—NR_(n1)R_(n2), andheterocyclyl are each as described herein, for example, whereapplicable, in any of (VIII1)-(VIII16).

(VIII19) In one embodiment, at least one R_(a2) is C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, OH, halogen,O—(CH₂)₁₋₄—NR_(n1)R_(n2), NR_(n1)—(CH₂)₁₋₄—NR_(n1)R_(n2), orheterocyclyl comprising one or two 4- to 6-membered rings and 1-4heteroatoms selected from N, O, and S, wherein the heterocyclyl isoptionally substituted with one or more R₁₁, wherein the C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halogen,O—(CH₂)₁₋₄—NR_(n1)R_(n2), NR_(n1)—(CH₂)₁—NR_(n1)R_(n2), and heterocyclylare each as described herein, for example, where applicable, in any of(VIII1)-(VIII16).

(VIII20) In one embodiment, at least one R_(a2) is C₁-C₆ alkyl, C₁-C₆alkoxy, OH, O—(CH₂)₁₋₄—NR_(n1)R_(n2), NR_(n1)—(CH₂)₁₋₄—NR_(n1)R_(n2), orheterocyclyl comprising one or two 4- to 6-membered rings and 1-4heteroatoms selected from N, O, and S, wherein the heterocyclyl isoptionally substituted with one or more R₁₁, wherein the C₁-C₆ alkyl,C₁-C₆ alkoxy, O—(CH₂)₁₋₄—NR_(n1)R_(n2), NR_(n1)—(CH₂)₁₋₄—NR_(n1)R_(n2),and heterocyclyl are each as described herein, for example, whereapplicable, in any of (VIII1)-(VIII16).

(VIII21) In one embodiment, at least one R_(a2) is C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, OH, halogen, or heterocyclylcomprising one or two 4- to 6-membered rings and 1-4 heteroatomsselected from N, O, and S, wherein the heterocyclyl is optionallysubstituted with one or more R₁₁, wherein the C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, halogen, and heterocyclyl areeach as described herein, for example, where applicable, in any of(VIII1)-(VIII16).

(VIII22) In one embodiment, at least one R_(a2) is C₃-C₈ cycloalkyl,heterocyclyl comprising one or two 4- to 6-membered rings and 1-4heteroatoms selected from N, O, and S, phenyl, or heteroaryl comprisingone or two 5- or 6-membered rings and 1-4 heteroatoms selected from N,O, and S, wherein the cycloalkyl, heterocyclyl, phenyl, or heteroaryl isoptionally substituted with one or more R₁₁, wherein the cycloalkyl,heterocyclyl, phenyl, and heteroaryl are each as described herein, forexample, where applicable, in any of (VIII1)-(VIII16).

(VIII23) In one embodiment, at least one R_(a2) is C₃-C₈ cycloalkyl orheterocyclyl comprising one or two 4- to 6-membered rings and 1-4heteroatoms selected from N, O, and S, wherein the cycloalkyl andheterocyclyl are each optionally substituted with one or more R₁₁,wherein the cycloalkyl and heterocyclyl are each as described herein,for example, where applicable, in any of (VIII1)-(VIII16).

(VIII24) In one embodiment, at least one R_(a2) is NH—C(O)—(C₁-C4alkyl). In one embodiment, at least one R_(a2) is NH—C(O)—CH₂CH₃.

(VIII25) In one embodiment, at least one R_(a2) is O-heterocyclyloptionally substituted with one or more R₁₁. In one embodiment, at leastone R_(a2) is

In one embodiment, at least one R_(a2) is

(VIII26) In one embodiment, at least one R_(a2) is C₁-C₆ alkyloptionally substituted with one or more R₁₁.

(IX1) In one embodiment, at least one R_(b2) is C₁-C₆ straight-chain orC₃-C₆ branched alkyl, including methyl, ethyl, n-propyl, i-propyl,n-butyl, i-butyl, s-butyl, t-butyl, pentyl, and hexyl. In a furtherembodiment, at least one R_(b2) is C₁-C₄ alkyl selected from methyl,ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, and t-butyl.

(IX2) In one embodiment, at least one R_(b2) is C₁-C₆ straight-chain orC₃-C₆ branched haloalkyl, including methyl, ethyl, n-propyl, i-propyl,n-butyl, i-butyl, s-butyl, t-butyl, pentyl, and hexyl, each of which issubstituted with one or more halogen (e.g., F, Cl, Br, or I). In afurther embodiment, at least one R_(b2) is C₁-C₄ haloalkyl selected frommethyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, andt-butyl, each of which is substituted with one or more halogen (e.g., F,Cl, Br, or I).

(IX3) In one embodiment, at least one R_(b2) is C₁-C₆ straight-chain orC₃-C₆ branched alkoxy, including methoxy, ethoxy, n-propoxy, i-propoxy,n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, and hexyloxy. In afurther embodiment, at least one R_(b2) is C₁-C₄ alkoxy selected frommethoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, andt-butoxy.

(IX4) In one embodiment, at least one R_(b2) is C₁-C₆ straight-chain orC₃-C₆ branched haloalkoxy, including methoxy, ethoxy, n-propoxy,i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, andhexyloxy, each of which is substituted with one or more halogen (e.g.,F, Cl, Br, or I). In a further embodiment, at least one R_(b2) is C₁-C₄haloalkoxy selected methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy,i-butoxy, s-butoxy, and t-butoxy, each of which is substituted with oneor more halogen (e.g., F, Cl, Br, or I).

(IX5) In one embodiment, at least one R_(b2) is OH.

(IX6) In one embodiment, at least one R_(b2) is halogen (e.g., F, Cl,Br, or I).

(IX7) In one embodiment, at least one R_(b2) is NH₂. In one embodiment,at least one R_(b2) is NR_(n3)R_(n4), wherein R_(n3) and R_(n4) are eachindependently C₁-C₄ alkyl selected from methyl, ethyl, n-propyl,i-propyl, n-butyl, i-butyl, s-butyl, and t-butyl.

(IX8) In one embodiment, at least one R_(b2) is heterocyclyl comprisingone 4- to 6-membered rings and 1 or 2 heteroatoms selected from N, O,and S. In one embodiment, at least one R_(b2) is azetidinyl.

(X1) In one embodiment, at least one R₈ is H.

(X2) In one embodiment, at least one R₈ is C₁-C₄ alkyl selected frommethyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, andt-butyl.

(X1) In one embodiment, each R₉ is independently C₂-C₄ alkenyl selectedfrom ethenyl, n-propenyl, i-propenyl, n-butenyl, i-butenyl, ands-butenyl, each of which is optionally substituted with one or more R₁₀.In a further embodiment, at least one R₉ is ethenyl or n-propenyl, eachof which is optionally substituted with one or more R₁₀.

(XII1) In one embodiment, each R₁₀ is independently NR_(n3)R_(n4),wherein R_(n3) and R_(n4) are each H.

(XII2) In one embodiment, each R₁₀ is independently NR_(n3)R_(n4),wherein R_(n3) and R_(n4) are each independently C₁-C₄ alkyl selectedfrom methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, andt-butyl.

(XIII1) In one embodiment, at least one R₁₁ is C₁-C₆ straight-chain orC₃-C₆ branched alkyl, including methyl, ethyl, n-propyl, i-propyl,n-butyl, i-butyl, s-butyl, t-butyl, pentyl, and hexyl. In a furtherembodiment, at least one R₁ is C₁-C₄ alkyl selected from methyl, ethyl,n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, and t-butyl. In a furtherembodiment, at least one R₁₁ is methyl.

(XIII2) In one embodiment, at least one R₁₁ is C₁-C₆ straight-chain orC₃-C₆ branched haloalkyl, including methyl, ethyl, n-propyl, i-propyl,n-butyl, i-butyl, s-butyl, t-butyl, pentyl, and hexyl, each of which issubstituted with one or more halogen (e.g., F, Cl, Br, or I). In afurther embodiment, at least one R₁₁ is C₁-C₄ haloalkyl selected frommethyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, andt-butyl, each of which is substituted with one or more halogen (e.g., F,Cl, Br, or I). In a further embodiment, at least one R₁₁ is CH₂F, CHF₂,or CF₃.

(XIII3) In one embodiment, at least one R₁₁ is C₁-C₆ straight-chain orC₃-C₆ branched alkoxy, including methoxy, ethoxy, n-propoxy, i-propoxy,n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, and hexyloxy. In afurther embodiment, at least one R₁₁ is C₁-C₄ alkoxy selected frommethoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, andt-butoxy. In a further embodiment, at least one R₁₁ is methoxy orethoxy.

(XIII4) In one embodiment, at least one R₁₁ is C₁-C₆ straight-chain orC₃-C₆ branched haloalkoxy, including methoxy, ethoxy, n-propoxy,i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, andhexyloxy, each of which is substituted with one or more halogen (e.g.,F, Cl, Br, or I). In a further embodiment, at least one R₁₁ is C₁-C₄haloalkoxy selected methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy,i-butoxy, s-butoxy, and t-butoxy, each of which is substituted with oneor more halogen (e.g., F, Cl, Br, or I). In a further embodiment, atleast one R₁₁ is OCH₂F, OCHF₂, or OCF₃.

(XIII5) In one embodiment, at least one R₁₁ is OH.

(XIII6) In one embodiment, least one R₁₁ is halogen (e.g., F, Cl, Br, orI) or CN. In one embodiment, at least one R₁₁ is halogen (e.g., F, Cl,Br, or I). In a further embodiment, at least one R₁₁ is F or Cl. In afurther embodiment, at least one R₁₁ is F. In one embodiment, least oneR₁₁ is CN.

(XIII7) In one embodiment, at least one R₁₁ is NH₂. In one embodiment,at least one R₁₁ is NR_(n3)R_(n4), wherein R_(n3) and R_(n4) are eachindependently C₁-C₄ alkyl selected from methyl, ethyl, n-propyl,i-propyl, n-butyl, i-butyl, s-butyl, and t-butyl.

(XIII8) In one embodiment, at least one R₁₁ is C₃-C₈ cycloalkyl selectedfrom cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, andcyclooctyl, each of which is optionally substituted with one or moreC₁-C₆ alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,s-butyl, t-butyl, pentyl, or hexyl).

(XIII9) In one embodiment, at least one R₁₁ is heterocyclyl comprisingone or two 4- to 6-membered rings and 1-4 heteroatoms selected from N,O, and S optionally substituted with one or more C₁-C₆ alkyl (e.g.,methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl,pentyl, or hexyl), halogen, or C(O)—(C₂-C₄ alkenyl) (e.g., C(O)—CH═CH₂).In one embodiment, at least one R₁₁ is heterocyclyl comprising one ortwo 5- to 6-membered rings and 1-4 heteroatoms selected from N, O, and Soptionally substituted with one or more C₁-C₆ alkyl (e.g., methyl,ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl,or hexyl), halogen, or C(O)—(C₂-C₄ alkenyl) (e.g., C(O)—CH═CH₂). In oneembodiment, at least one R₁₁ is heterocyclyl comprising one or two 5- to6-membered rings and 1-4 heteroatoms selected from N, O, and Soptionally substituted with one or more C₁-C₆ alkyl (e.g., methyl,ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl,or hexyl). In a further embodiment, at least one R₁₁ is heterocyclylcomprising one 5- to 6-membered ring and 1-4 heteroatoms selected fromN, O, and S (e.g., pyrrolidinyl, tetrahydrofuranyl,tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl,isoxazolidinyl, thiazolidinyl, isothiazolidinyl, triazolidinyl,oxadiazolidinyl, isoxadiazolidinyl, thiadiazolidinyl,isothiadiazolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl,hexahydropyridazinyl, hexahydropyrimidinyl, morpholinyl, triazinanyl,etc.) optionally substituted with one or more C₁-C₆ alkyl (e.g., methyl,ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl,or hexyl). In a further embodiment, at least one R₁₁ is pyrrolidinyl,piperidinyl, or piperazinyl optionally substituted with one or moreC₁-C₆ alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,s-butyl, t-butyl, pentyl, or hexyl). In one embodiment, at least one R₁₁heterocyclyl comprising one or two 5- to 6-membered rings and 1-4heteroatoms selected from N, O, and S optionally substituted with one ormore halogen (e.g., F, Cl, or Br). In one embodiment, at least one R₁₁heterocyclyl comprising one or two 5- to 6-membered rings and 1-4heteroatoms selected from N, O, and S optionally substituted with one ormore F. In one embodiment, at least one R₁₁ is heterocyclyl comprisingone or two 5- to 6-membered rings and 1-4 heteroatoms selected from N,O, and S optionally substituted with one or more C(O)—(C₂-C₄ alkenyl)(e.g., C(O)—CH═CH₂).

(XIV1) In one embodiment, R₃ is phenyl or naphthyl optionallysubstituted with one or more R₇.

(XIV2) In one embodiment, R₃ is heteroaryl comprising one or two 5- or6-membered rings and 1-4 heteroatoms selected from N, O, and S (e.g.,pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl,thiadiazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, pyranyl, thiopyranyl, diazinyl, thiazinyl, dioxinyl,triazinyl, indolyl, indolonyl, isoindolyl, isoindolonyl,pyridopyridinyl, pyridopyrimidinyl, quinolinyl, quinazolinyl, etc.)optionally substituted with one or more R₇. In a further embodiment, R₃is heteroaryl comprising one 5- or 6-membered ring and 1-4 heteroatomsselected from N, O, and S (e.g., pyrrolyl, furanyl, thiophenyl,pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl,pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, thiopyranyl, diazinyl,thiazinyl, dioxinyl, triazinyl, etc.) optionally substituted with one ormore RT. In a further embodiment, R₃ is pyrrolyl, imidazolyl, pyrazolyl,pyridinyl, oxazolyl, isoxazolyl, indolyl, or indolonyl, each of which isoptionally substituted with one or more R₇.

(XV1) In one embodiment, at least one R₇ is C₁-C₆ straight-chain orC₃-C₆ branched alkyl, including methyl, ethyl, n-propyl, i-propyl,n-butyl, i-butyl, s-butyl, t-butyl, pentyl, and hexyl. In a furtherembodiment, at least one R₇ is C₁-C₄ alkyl selected from methyl, ethyl,n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, and t-butyl. In a furtherembodiment, at least one R₇ is methyl.

(XV2) In one embodiment, at least one R₇ is C₁-C₆ straight-chain orC₃-C₆ branched haloalkyl, including methyl, ethyl, n-propyl, i-propyl,n-butyl, i-butyl, s-butyl, t-butyl, pentyl, and hexyl, each of which issubstituted with one or more halogen (e.g., F, Cl, Br, or I). In afurther embodiment, at least one R₇ is C₁-C₄ haloalkyl selected frommethyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, andt-butyl, each of which is substituted with one or more halogen (e.g., F,Cl, Br, or I).

(XV3) In one embodiment, at least one R₇ is C₁-C₆ straight-chain orC₃-C₆ branched alkoxy, including methoxy, ethoxy, n-propoxy, i-propoxy,n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, and hexyloxy. In afurther embodiment, at least one R₇ is C₁-C₄ alkoxy selected frommethoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, andt-butoxy.

(XV4) In one embodiment, at least one R₇ is C₁-C₆ straight-chain orC₃-C₆ branched haloalkoxy, including methoxy, ethoxy, n-propoxy,i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, andhexyloxy, each of which is substituted with one or more halogen (e.g.,F, Cl, Br, or I). In a further embodiment, at least one R₇ is C₁-C₄haloalkoxy selected methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy,i-butoxy, s-butoxy, and t-butoxy, each of which is substituted with oneor more halogen (e.g., F, Cl, Br, or I).

(XV5) In one embodiment, at least one R₇ is OH.

(XV6) In one embodiment, at least one R₇ is halogen (e.g., F, Cl, Br, orI). In a further embodiment, at least one R₇ is F or Cl. In a furtherembodiment, at least one R₇ is F.

(XV7) In one embodiment, at least one R₇ is CN.

(XV8) In one embodiment, at least one R₇ is NH₂. In one embodiment, atleast one R₇ is NR_(n3)R_(n4), wherein R_(n3) and R_(n4) are eachindependently C₁-C₄ alkyl selected from methyl, ethyl, n-propyl,i-propyl, n-butyl, i-butyl, s-butyl, and t-butyl.

(XVI1) In one embodiment, R₄ is H.

(XVI2) In one embodiment, R₄ is C₁-C₄ alkyl selected from methyl, ethyl,n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, and t-butyl.

(XVII1) In one embodiment, R₅ is H.

(XVII2) In one embodiment, R₅ is C₁-C₄ alkyl selected from methyl,ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, and t-butyl.

(XVII1) In one embodiment, R₆ is H.

(XVII2) In one embodiment, R₆ is C₁-C₄ alkyl selected from methyl,ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, and t-butyl.

(XIX1) In one embodiment, W is NR₈C(O)R₉ or C(O)R₉.

(XIX2) In one embodiment, W is selected from formulae (i-1)-(i-5),(i-9)-(i-16), (i-18), (i-19), (i-28), (i-29), and (i-36)-(i-39).

(XIX3) In one embodiment, W is selected from formulae (i-1), (i-3),(i-9), (i-13), (i-14), (i-16), (i-18), (i-19), (i-29), and(i-36)-(i-39).

(XIX4) In one embodiment, W is selected from formulae (i-2), (i-10),(i-15), (i-28), and (i-34).

(XIX5) In one embodiment, W is selected from formulae (i-4), (i-5), and(i-10).

(XIX6) In one embodiment, W is selected from formulae (i-11) and (i-12).

(XIX7) In one embodiment, W is selected from formulae (i-6)-(i-8),(i-17), (i-20)-(i-27), (i-30)-(i-35), (i-40), and (i-41).

(XIX8) In one embodiment, W is selected from formulae (i-6)-(i-8),(i-17), (i-20)-(i-27), (i-30), (i-34), (i-40), and (i-41).

Any of the substituents described herein for any of R₁, R₂, R₂′, R₃, R₄,R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R_(a1), R_(a2), R_(b1), R_(b2), R_(n1),R_(n2), R_(n3), R_(n4), W, and Q can be combined with any of thesubstituents described herein for one or more of the remainder of R₁,R₂, R₂′, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R_(a1), R_(a2), R_(b1),R_(b2), R_(n1), R_(n2), R_(n3), R_(n4), W, and Q.

(1) In one embodiment, R₁, R₂, R₂′, and Q are each as defined, whereapplicable, in any of (I1)-(III4), R₃ is as defined in (XIV1).

(2) In one embodiment, R₁, R₂, R₂′, and Q are each as defined, whereapplicable, in any of (I1)-(III4), R₃ is as defined in (XIV2).

(3) In one embodiment, R₁ and R₂ are each as defined, where applicable,in any of (V1)-(VII2), R₃ is as defined in (XIV1).

(4) In one embodiment, R₁ and R₂ are each as defined, where applicable,in any of (V1)-(VII2), R₃ is as defined in (XIV2).

(5) In one embodiment, R₁, R₂, R₂′, R₃, and Q are each as defined, whereapplicable, in any of (1)-(4), R₅ is as defined in (XVIII).

(6) In one embodiment, R₁, R₂, R₂′, R₃, and Q are each as defined, whereapplicable, in any of (1)-(4), R₅ is as defined in (XVII2).

(7) In one embodiment, R₁, R₂, R₂′, R₃, R₅, and Q are each as defined,where applicable, in any of (1)-(6), R₆ is as defined in (XVIII1).

(8) In one embodiment, R₁, R₂, R₂′, R₃, R₅, and Q are each as defined,where applicable, in any of (1)-(6), R₆ is as defined in (XVIII2).

(9) In one embodiment, R₁, R₂, R₂′, R₃, R₅, R₆, and Q are each asdefined, where applicable, in any of (1)-(8), R₄ is as defined in(XVI1).

(10) In one embodiment, R₁, R₂, R₂′, R₃, R₅, R₆, and Q are each asdefined, where applicable, in any of (1)-(8), R₄ is as defined in(XVI2).

(11) In one embodiment, R₁, R₂, R₂′, and Q are each as defined, whereapplicable, in any of (I1)-(III4), R_(a1) is as defined in (IV16).

(12) In one embodiment, R₁, R₂, R₂′, and Q are each as defined, whereapplicable, in any of (I1)-(III4), R_(a1) is as defined in (IV17).

(13) In one embodiment, R₁, R₂, R₂′, and Q are each as defined, whereapplicable, in any of (I1)-(III4), R_(a1) is as defined in (IV18).

(14) In one embodiment, R₁, R₂, R₂′, and Q are each as defined, whereapplicable, in any of (I1)-(III4), R_(a1) is as defined in (IV19).

(15) In one embodiment, R₁, R₂, R₂′, and Q are each as defined, whereapplicable, in any of (I1)-(III4), R_(a1) is as defined in (IV20).

(16) In one embodiment, R₁, R₂, R₂′, and Q are each as defined, whereapplicable, in any of (I1)-(III4), R_(a1) is as defined in (IV21).

(17) In one embodiment, R₁, R₂, R₂′, and Q are each as defined, whereapplicable, in any of (I1)-(III4), R_(a1) is as defined in (IV22).

(18) In one embodiment, R₁, R₂, R₂′, and Q are each as defined, whereapplicable, in any of (I1)-(III4), R_(a1) is as defined in (IV23).

(19) In one embodiment, R₁, R₂, R₂′, R_(a1), and Q are each as defined,where applicable, in any of (I1)-(III4) and (11)-(18), R_(b1) is asdefined in (V1).

(20) In one embodiment, R₁, R₂, R₂′, R_(a1), and Q are each as defined,where applicable, in any of (I1)-(III4) and (11)-(18), R_(b1) is asdefined in (V2).

(21) In one embodiment, R₁, R₂, R₂′, R_(a1), and Q are each as defined,where applicable, in any of (I1)-(III4) and (11)-(18), R_(b1) is asdefined in (V3).

(22) In one embodiment, R₁, R₂, R₂′, R_(a1), and Q are each as defined,where applicable, in any of (I1)-(III4) and (11)-(18), R_(b1) is asdefined in (V4).

(23) In one embodiment, R₁, R₂, R₂′, R_(a1) and Q are each as defined,where applicable, in any of (I1)-(III4) and (11)-(18), R_(b1) is asdefined in (V5).

(24) In one embodiment, R₁, R₂, R₂′, R_(a1), and Q are each as defined,where applicable, in any of (I1)-(III4) and (11)-(18), R_(b1) is asdefined in (V6).

(25) In one embodiment, R₁, R₂, R₂′, R_(a1), and Q are each as defined,where applicable, in any of (I1)-(III4) and (11)-(18), R_(b1) is asdefined in (V7).

(26) In one embodiment, R₁, R₂, R₂′, R_(a1), and Q are each as defined,where applicable, in any of (I1)-(III4) and (11)-(18), R_(b1) is asdefined in (V8).

(27) In one embodiment, R₁ and R₂ are each as defined, where applicable,in any of (VI1)-(VII2), R_(a2) is as defined in (VIII17).

(28) In one embodiment, R₁ and R₂ are each as defined, where applicable,in any of (VI1)-(VII2), R_(a2) is as defined in (VIII18).

(29) In one embodiment, R₁ and R₂ are each as defined, where applicable,in any of (VI1)-(VII2), R_(a2) is as defined in (VIII19).

(30) In one embodiment, R₁ and R₂ are each as defined, where applicable,in any of (VI1)-(VII2), R_(a2) is as defined in (VIII20).

(31) In one embodiment, R₁ and R₂ are each as defined, where applicable,in any of (VI1)-(VII2), R_(a2) is as defined in (VIII21).

(32) In one embodiment, R₁ and R₂ are each as defined, where applicable,in any of (VI1)-(VII2), R_(a2) is as defined in (VIII22).

(33) In one embodiment, R₁ and R₂ are each as defined, where applicable,in any of (VI1)-(VII2), R_(a2) is as defined in (VIII23).

(34) In one embodiment, R₁ and R₂ are each as defined, where applicable,in any of (VI1)-(VII2), R_(a2) is as defined in (VIII24).

(35) In one embodiment, R₁ and R₂ are each as defined, where applicable,in any of (VI1)-(VII2), R_(a2) is as defined in (VIII25).

(36) In one embodiment, R₁ and R₂ are each as defined, where applicable,in any of (VI1)-(VII2), R_(a2) is as defined in (VIII26).

(37) In one embodiment, R₁, R₂, and R_(a2) are each as defined, whereapplicable, in any of (VI1)-(VII2) and (27)-(36), R_(b2) is as definedin (IX1).

(38) In one embodiment, R₁, R₂, and R_(a2) are each as defined, whereapplicable, in any of (VI1)-(VII2) and (27)-(36), R_(b2) is as definedin (IX2).

(39) In one embodiment, R₁, R₂, and R_(a2) are each as defined, whereapplicable, in any of (VI1)-(VII2) and (27)-(36), R_(b2) is as definedin (IX3).

(40) In one embodiment, R₁, R₂, and R_(a2) are each as defined, whereapplicable, in any of (VI1)-(VII2) and (27)-(36), R_(b2) is as definedin (IX4).

(41) In one embodiment, R₁, R₂, and R_(a2) are each as defined, whereapplicable, in any of (VI1)-(VII2) and (27)-(36), R_(b2) is as definedin (IX5).

(42) In one embodiment, R₁, R₂, and R_(a2) are each as defined, whereapplicable, in any of (VI1)-(VII2) and (27)-(36), R_(b2) is as definedin (IX6).

(43) In one embodiment, R₁, R₂, and R_(a2) are each as defined, whereapplicable, in any of (VI1)-(VII2) and (27)-(36), R_(b2) is as definedin (IX7).

(44) In one embodiment, R₁, R₂, and R_(a2) are each as defined, whereapplicable, in any of (VI1)-(VII2) and (27)-(36), R_(b2) is as definedin (IX8).

(45) In one embodiment, R₁, R₂, R₂′, R_(a1), R_(b1), R_(a2), R_(b2), andQ are each as defined, where applicable, in any of (11)-(44), R₃ is asdefined in (XIV1).

(46) In one embodiment, R₁, R₂, R₂′, R_(a1), R_(b1), R_(a2), R_(b2), andQ are each as defined, where applicable, in any of (11)-(44), R₃ is asdefined in (XIV2).

(47) In one embodiment, R₁, R₂, R₂′, R₃, R_(a1), R_(b1), R_(a2), R_(b2),and Q are each as defined, where applicable, in any of (11)-(46), R₅ isas defined in (XVII1).

(48) In one embodiment, R₁, R₂, R₂′, R₃, R_(a1), R_(b1), R_(a2), R_(b2),and Q are each as defined, where applicable, in any of (11)-(46), R₈ isas defined in (XVII2).

(49) In one embodiment, R₁, R₂, R₂′, R₃, R_(a1), R_(b1), R_(a2), R_(b2),R₅, and Q are each as defined, where applicable, in any of (11)-(48), R₆is as defined in (XVIII1).

(50) In one embodiment, R₁, R₂, R₂′, R₃, R_(a1), R_(b1), R_(a2), R_(b2),R₅, and Q are each as defined, where applicable, in any of (11)-(48), R₆is as defined in (XVIII2).

(51) In one embodiment, R₁, R₂, R₂′, R₃, R_(a1), R_(b1), R_(a2), R_(b2),R₅, R₆, and Q are each as defined, where applicable, in any of(11)-(50), R₄ is as defined in (XVI1).

(52) In one embodiment, R₁, R₂, R₂′, R₃, R_(a1), R_(b1), R_(a2), R_(b2),R₅, R₆, and Q are each as defined, where applicable, in any of(11)-(50), R₄ is as defined in (XVI2).

(53) In one embodiment, R₁, R₂, R₂′, R₃, R₄, R_(a1), R_(b1), R_(a2),R_(b2), R₅, R₆, and Q are each as defined, where applicable, in any of(1)-(452), W is as defined in (XIX1).

(54) In one embodiment, R₁, R₂, R₂′, R₃, R₄, R_(a1), R_(b1), R_(a2),R_(b2), R₅·R₆, and Q are each as defined, where applicable, in any of(1)-(52), W is as defined in (XIX2).

(55) In one embodiment, R₁, R₂, R₂′, R₃, R₄, R_(a1), R_(b1), R_(a2),R_(b2), R₅, R₆, and Q are each as defined, where applicable, in any of(1)-(52), W is as defined in (XIX3).

(56) In one embodiment, R₁, R₂, R₂′, R₃, R₄, R_(a1), R_(b1), R_(a2),R_(b2), R₅, R₆, and Q are each as defined, where applicable, in any of(1)-(52), W is as defined in (XIX4).

(57) In one embodiment, R₁, R₂, R₂′, R₃, R₄, R_(a1), R_(b1), R_(a2),R_(b2), R₅, R₆, and Q are each as defined, where applicable, in any of(1)-(52), W is as defined in (XIX5).

(58) In one embodiment, R₁, R₂, R₂′, R₃, R₄, R_(a1), R_(b1), R_(a2),R_(b2), R₅, R₆, and Q are each as defined, where applicable, in any of(1)-(52), W is as defined in (XIX6).

(59) In one embodiment, R₁, R₂, R₂′, R₃, R₄, R_(a1), R_(b1), R_(a2),R_(b2), R₅, R₆, and Q are each as defined, where applicable, in any of(1)-(52), W is as defined in (XIX7).

(60) In one embodiment, R₁, R₂, R₂′, R₃, R₄, R_(a1), R_(b1), R_(a2),R_(b2), R₅, R₆, and Q are each as defined, where applicable, in any of(1)-(52), W is as defined in (XIX8).

In one embodiment, a compound of Formula I is of Formula Ia, Ia1, orIa2;

or a pharmaceutically acceptable salt thereof, wherein:

R₁, R₃, R₇, R₈, R₉, R₁₀, R₁₁, R_(a1), R_(b2), R_(n1), R_(n2), R_(n3),and R_(n4) are each as defined herein above in Formula I′ or Formula I;

X is N or CH; and

p1 is 0, 1, 2, or 3.

(a1) In one embodiment, X is N.

(a2) In one embodiment, X is CH.

(a3) In one embodiment, p1 is 0.

(a4) In one embodiment, p1 is 1, 2, or 3.

In one embodiment, R₁, R₃, R₇, R₈, R₉, R₁₀, R₁₁, R_(a1), R_(b2), R_(n1),R_(n2), R_(n3), and R_(n4) can each be selected from any of thesubstituents as described herein, for example, in Formula I′ or FormulaI.

Any of the substituents described herein for any of R₁, R₃, R₇, R₈, R₉,R₁₀, R₁₁, R_(a1), R_(b2), R_(n1), R_(n2), R_(n3), R_(n4), p1, and X, forexample, in any of Formulae I, Ia, Ia1, and Ia2, can be combined withany of the substituents described herein for one or more of theremainder of R₁, R₃, R₇, R₈, R₉, R₁₀, R₁₁, R_(a1), R_(b2), R_(n1),R_(n2), R_(n3), R_(n4), p1, and X, for example, in any of Formulae I,Ia, Ia1, and Ia2.

(a5) In one embodiment, p1 is 0 and X is N.

(a6) In one embodiment, p1 is 0 and X is CH.

(a7) In one embodiment, p1 is 1, 2, or 3, and X is N.

(a8) In one embodiment, p1 is 1, 2, or 3, and X is CH.

(a9) In one embodiment, X and p1 are each as defined, where applicable,in any of (a1)-(a8), and R₁ is phenyl optionally substituted with one ormore R_(a1).

(a10) In one embodiment, X and p1 are each as defined, where applicable,in any of (a1)-(a8), and R₁ is heteroaryl comprising one or two 5- or6-membered rings and 1-4 heteroatoms selected from N, O, and Soptionally substituted with one or more R_(a1). In a further embodiment,R₁ is heteroaryl comprising one 5- or 6-membered ring and 1-4heteroatoms selected from N, O, and S (e.g., pyrrolyl, furanyl,thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl,pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, thiopyranyl,diazinyl, thiazinyl, dioxinyl, triazinyl, etc.) optionally substitutedwith one or more R_(a1). In a further embodiment, R₁ is heteroarylcomprising one 5-membered ring and 1-4 heteroatoms selected from N, O,and S (e.g., pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl,oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl,thiadiazolyl, tetrazolyl, etc.) optionally substituted with one or moreR_(a1). In a further embodiment, R₁ is pyrazolyl or pyridinyl optionallysubstituted with one or more R_(a1). In a further embodiment, R₁ ispyrazolyl optionally substituted with one or more R_(a1).

(a11) In one embodiment, p1 is 0; X is N; and R₁ is heteroarylcomprising one or two 5- or 6-membered rings and 1-4 heteroatomsselected from N, O, and S optionally substituted with one or moreR_(a1). In a further embodiment, R₁ is heteroaryl comprising one 5- or6-membered ring and 1-4 heteroatoms selected from N, O, and S (e.g.,pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl,thiadiazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, pyranyl, thiopyranyl, diazinyl, thiazinyl, dioxinyl,triazinyl, etc.) optionally substituted with one or more R_(a1). In afurther embodiment, R₁ is heteroaryl comprising one 5-membered ring and1-4 heteroatoms selected from N, O, and S (e.g., pyrrolyl, furanyl,thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, etc.)optionally substituted with one or more R_(a1). In a further embodiment,R₁ is pyrazolyl or pyridinyl optionally substituted with one or moreR_(a1). In a further embodiment, R₁ is pyrazolyl optionally substitutedwith one or more R_(a1).

(a12) In one embodiment, p1 is 0; X is CH; and R₁ is heteroarylcomprising one or two 5- or 6-membered rings and 1-4 heteroatomsselected from N, O, and S optionally substituted with one or moreR_(a1). In a further embodiment, R₁ is heteroaryl comprising one 5- or6-membered ring and 1-4 heteroatoms selected from N, O, and S (e.g.,pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl,thiadiazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, pyranyl, thiopyranyl, diazinyl, thiazinyl, dioxinyl,triazinyl, etc.) optionally substituted with one or more R_(a1). In afurther embodiment, R₁ is heteroaryl comprising one 5-membered ring and1-4 heteroatoms selected from N, O, and S (e.g., pyrrolyl, furanyl,thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, etc.)optionally substituted with one or more R_(a1). In a further embodiment,R₁ is pyrazolyl or pyridinyl optionally substituted with one or more R₁.In a further embodiment, R₁ is pyrazolyl optionally substituted with oneor more R_(a1).

In one embodiment, a compound of Formula I is of Formula Ib or Ib1:

or a pharmaceutically acceptable salt thereof, wherein:

R₁, R₃, R₇, R₉, R₁₀, R₁₁, R_(a1), R_(b2), R_(n1), R_(n2), R_(n3),R_(n4), and Q are each as defined herein above in Formula I′ or FormulaI;

m is 0, 1, 2, or 3:

n is 0, 1, or 2; and

p2 is 0, 1, 2, or 3.

In one embodiment, when m and n are each 1, and R3 is substitutedphenyl, then R₁ is not substituted phenyl.

(b1) In one embodiment, p2 is 0.

(b2) In one embodiment, p2 is 1, 2, or 3.

(b3) In one embodiment, n is 1 or 2.

(b4) In one embodiment, n is 1 or 2; and m is 0.

(b5) In one embodiment, n is 1 or 2; and m is 1.

(b6) In one embodiment, n is 1 or 2; and m is 2.

(b7) In one embodiment, n is 1 or 2; and m is 3.

(b8) In one embodiment, n is 1.

(b9) In one embodiment, n is 1; and m is 0.

(b10) In one embodiment, n is 1; and m is 1.

(b11) In one embodiment, n is 1; and m is 2.

(b12) In one embodiment, n is 1; and m is 3.

(b13) In one embodiment, n is 0; and m is 0.

(b14) In one embodiment, n is 0; and m is 1.

(b15) In one embodiment, n is 0; and m is 2.

(b16) In one embodiment, n is 0; and m is 3.

(b17) Q is (CH₂)₀.

(b18) Q is (CH₂)₁₋₃.

(b19) Q is (CH₂)₁.

In one embodiment, R₁, R₃, R₇, R₉, R₁₀, R₁₁, R_(a1), R_(b2), R_(n1),R_(n2), R_(n3), and R_(n4) can each be selected from any of thesubstituents as described herein, for example, in Formula I′ or FormulaI.

Any of the substituents described herein for any of R₁, R₃, R₇, R₉, R₁₀,R₁₁, R_(a1), R_(b2), R_(n1), R_(n2), R_(n3), R_(n4), Q, p2, m, and n,for example, in any of Formulae I, Ib, and Ib1, can be combined with anyof the substituents described herein for one or more of the remainder ofR₁, R₃, R₇, R₉, R₁₀, R₁₁, R_(a1), R_(b2), R_(n1), R_(n2), R_(n3),R_(n4), Q, p2, m, and n, for example, in any of Formulae I, Ib, and Ib1.

(b20) In one embodiment, p2 is as defined in (b1) or (b2), and m and nare each as defined, where applicable, in any of (b3)-(b16).

(b21) In one embodiment, Q is as defined in (b17), p2 is as defined in(b1) or (b2), and m and n are each as defined, where applicable, in anyof (b3)-(b16).

(b22) In one embodiment, Q is as defined in (b17), p2 is as defined in(b1) or (b2), and m and n are each as defined, where applicable, in anyof (b3)-(b12).

(b23) In one embodiment, Q is as defined in (b18), p2 is as defined in(b1) or (b2), and m and n are each as defined, where applicable, in anyof (b3)-(b16).

(b24) In one embodiment, Q is as defined in (b19), p2 is as defined in(b1) or (b2), and m and n are each as defined, where applicable, in anyof (b3)-(b16).

(b25) In one embodiment, p2, m, n, and Q are each as defined, whereinapplicable, in any of (b1)-(b24), and R₁ is phenyl optionallysubstituted with one or more R_(a1).

(b26) In one embodiment, p2, m, n, and Q are each as defined, whereinapplicable, in any of (b1)-(b24), and R₁ is heteroaryl comprising one ortwo 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and Soptionally substituted with one or more R_(a1). In a further embodiment,R₁ is heteroaryl comprising one 5- or 6-membered ring and 1-4heteroatoms selected from N, O, and S (e.g., pyrrolyl, furanyl,thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl,pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, thiopyranyl,diazinyl, thiazinyl, dioxinyl, triazinyl, etc.) optionally substitutedwith one or more R_(a1). In a further embodiment, R₁ is heteroarylcomprising one 5-membered ring and 1-4 heteroatoms selected from N, O,and S (e.g., pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl,oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl,thiadiazolyl, tetrazolyl, etc.) optionally substituted with one or moreR_(a1). In a further embodiment, R₁ is pyrazolyl or pyridinyl optionallysubstituted with one or more R_(a1). In a further embodiment, R₁ ispyrazolyl optionally substituted with one or more R_(a1).

In one embodiment, a compound of Formula I is of Formula Ic or Ic1:

or a pharmaceutically acceptable salt thereof, wherein:

R₁, R₃, R₇, R₈, R₉, R₁₀, R₁₁, R_(a1), R_(b2), R_(n1), R_(n2), R_(n3),and R_(n4) are each as defined herein above in Formula I′ or Formula I;

m is 0, 1, 2, or 3; and

p2 is 0, 1, 2, or 3.

(c1) In one embodiment, p2 is 0.

(c2) In one embodiment, p2 is 1, 2, or 3.

(c3) In one embodiment, m is 0.

(c4) In one embodiment, m is 1.

(c5) In one embodiment, m is 2.

(c6) In one embodiment, m is 3.

In one embodiment, R₁, R₃, R₇, R₈, R₉, R₁₀, R₁₁, R_(a1), R_(b2), R_(n1),R_(n2), R_(n3), and R_(n4) can each be selected from any of thesubstituents as described herein, for example, in Formula I′ or FormulaI.

Any of the substituents described herein for any of R₁, R₃, R₇, R₈, R₉,R₁₀, R₁₁, R_(a1), R_(b2), R_(n1), R_(n2), R_(n3), R_(n4), p2, and m, forexample, in any of Formulae I, Ic, and Ic1, can be combined with any ofthe substituents described herein for one or more of the remainder ofR₁, R₃, R₇, R₈, R₉, R₁₀, R₁₁, R_(a1), R_(b2), R_(n1), R_(n2), R_(n3),R_(n4), p2, and m, for example, in any of Formulae I, Ic, and Ic1.

(c7) In one embodiment, p2 is 0, and m is 0.

(c8) In one embodiment, p2 is 0, and m is 1.

(c9) In one embodiment, p2 is 0, and m is 2.

(c10) In one embodiment, p2 is 0, and m is 3.

(c11) In one embodiment, p2 is 1, and m is 0.

(c12) In one embodiment, p2 is 1, and m is 1.

(c13) In one embodiment, p2 is 1, and m is 2.

(c14) In one embodiment, p2 is 1, and m is 3.

(c15) In one embodiment, p2 and m are each as defined, whereinapplicable, in any of (c1)-(c14), and R₁ is phenyl optionallysubstituted with one or more R_(a1).

(c16) In one embodiment, p2 and m are each as defined, whereinapplicable, in any of (c1)-(c14), and R₁ is heteroaryl comprising one ortwo 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and Soptionally substituted with one or more R_(a1). In a further embodiment,R₁ is heteroaryl comprising one 5- or 6-membered ring and 1-4heteroatoms selected from N, O, and S (e.g., pyrrolyl, furanyl,thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl,pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, thiopyranyl,diazinyl, thiazinyl, dioxinyl, triazinyl, etc.) optionally substitutedwith one or more R_(a1). In a further embodiment, R₁ is heteroarylcomprising one 5-membered ring and 1-4 heteroatoms selected from N, O,and S (e.g., pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl,oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl,thiadiazolyl, tetrazolyl, etc.) optionally substituted with one or moreR_(a1). In a further embodiment, R₁ is pyrazolyl or pyridinyl optionallysubstituted with one or more R_(a1). In a further embodiment, R₁ ispyrazolyl optionally substituted with one or more R_(a1).

In one embodiment, a compound of Formula I is of Formula Id, Id1, Id2,or Id3:

or a pharmaceutically acceptable salt thereof, wherein:

R₂, R₃, R₇, R₈, R₉, R₁₀, R₁₁, R_(a1), R_(b2), R_(n1), R_(n2), R_(n3),and R_(n4) are each as defined herein above in Formula I′ or Formula I;

X is N or CH;

R_(a1)′ is C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy,OH, or halogen; and

p3 is 0, 1, 2, or 3.

(d1) In one embodiment, X is N.

(d2) In one embodiment, X is CH.

(d3) In one embodiment, p3 is 0.

(d4) In one embodiment, p3 is 1.

(d5) In one embodiment, p3 is 2.

(d6) In one embodiment, p3 is 3.

(d7) In one embodiment, R_(a1)′ is C₁-C₆ straight-chain or C₃-C₆branched alkyl, including methyl, ethyl, n-propyl, i-propyl, n-butyl,i-butyl, s-butyl, t-butyl, pentyl, and hexyl. In a further embodiment,R_(a1)′ is C₁-C₄ alkyl selected from methyl, ethyl, n-propyl, i-propyl,n-butyl, i-butyl, s-butyl, and t-butyl. In a further embodiment, R_(a1)′is methyl.

(d8) In one embodiment, R_(a1)′ is C₁-C₆ straight-chain or C₃-C₆branched haloalkyl, including methyl, ethyl, n-propyl, i-propyl,n-butyl, i-butyl, s-butyl, t-butyl, pentyl, and hexyl, each of which issubstituted with one or more halogen (e.g., F, Cl, Br, or I). In afurther embodiment, R_(a1)′ is C₁-C₄ haloalkyl selected from methyl,ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, and t-butyl, eachof which is substituted with one or more halogen (e.g., F, Cl, Br, orI). In a further embodiment, R_(a1)′ is CH₂F, CHF₂, or CF₃.

(d9) In one embodiment, R_(a1)′ is C₁-C₆ straight-chain or C₃-C₆branched alkoxy, including methoxy, ethoxy, n-propoxy, i-propoxy,n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, and hexyloxy. In afurther embodiment, R_(a1)′ is C₁-C₄ alkoxy selected from methoxy,ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, andt-butoxy. In a further embodiment, R_(a1)′ is methoxy or ethoxy.

(d10) In one embodiment, R_(a1)′ is C₁-C₆ straight-chain or C₃-C₆branched haloalkoxy, including methoxy, ethoxy, n-propoxy, i-propoxy,n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, and hexyloxy, each ofwhich is substituted with one or more halogen (e.g., F, Cl, Br, or I).In a further embodiment, R_(a1)′ is C₁-C₄ haloalkoxy selected methoxy,ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, andt-butoxy, each of which is substituted with one or more halogen (e.g.,F, Cl, Br, or I). In a further embodiment, R_(a1)′ is OCH₂F, OCHF₂, orOCF₃.

(d11) In one embodiment, R_(a1)′ is OH.

(d12) In one embodiment, R_(a1)′ is halogen (e.g., F, Cl, Br, or I). Ina further embodiment, R_(a1)′ is F or Cl. In a further embodiment,R_(a1)′ is F.

In one embodiment, R₂, R₃, R₇, R₈, R₉, R₁₀, R₁₁, R_(a1), R_(b2), R_(n1),R_(n2), R_(n3), and R_(n4) can each be selected from any of thesubstituents as described herein, for example, in Formula I′ or FormulaI.

Any of the substituents described herein for any of R₂, R₃, R₇, R₈, R₉,R₁₀, R₁₁, R_(a1), R_(b2), R_(n1), R_(n2), R_(n3), R_(n4), R_(a1)′, X,and p3, for example, in any of Formulae I, Id, Id1, Id2, and Id3, can becombined with any of the substituents described herein for one or moreof the remainder of R₂, R₃, R₇, R₈, R₉, R₁₀, R₁₁, R_(a1), R_(b2),R_(n1), R_(n2), R_(n3), R_(n4), R_(a1)′, X, and p3, for example, in anyof Formulae I, Id, Id1, Id2, and Id3.

(d13) In one embodiment, X is N, and p3 is as defined in any of(d4)-(d6).

(d14) In one embodiment, X is CH, and p3 is as defined in any of(d4)-(d6).

(d15) In one embodiment, X is N, and p3 is as defined in any of (d3).

(d16) In one embodiment, X is CH, and p3 is as defined in any of (d3).

(d17) In one embodiment, X, p3, and R_(a1)′ are each as defined, whereapplicable, in any of (d1)-(d16), and R₂ is C₁-C₄ alkyl selected frommethyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, andt-butyl, each of which is optionally substituted with one or moreR_(b2). In a further embodiment, R₂ is methyl optionally substitutedwith one or more R_(b2). In a further embodiment, R₂ is methyl.

(d18) In one embodiment, X, p3, and R_(a1)′ are each as defined, whereapplicable, in any of (d1)-(d16), and R₂ is C₃-C₈ cycloalkyl selectedfrom cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, andcyclooctyl, each of which is optionally substituted with one or moreR_(b2). In a further embodiment, R₂ is cyclobutyl, cyclopentyl, orcyclohexyl, each of which is optionally substituted with one or moreR_(b2).

(d19) In one embodiment, X, p3, R_(a1)′, and R₂ are each as defined,where applicable, in any of (d1), (d2), (d4)-(d14), (d17), and (d18),and at least one R_(a1) is O—(CH₂)₁₋₄—NR_(n1)R_(n2) orNR_(n1)—(CH₂)₁₋₄—NR_(n1)R_(n2), wherein each R_(a1) and R_(n4) are H. Inone embodiment, at least one R_(a1) is O—(CH₂)₁₋₄—NR_(n1)R_(n2) orNR_(n1)—(CH₂)₁₋₄—NR_(n1)R_(n2), wherein each Ran is independently H orC₁-C₄ alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,s-butyl, or t-butyl), and R_(n2) is C₁-C₄ alkyl (e.g., methyl, ethyl,n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl). In oneembodiment, at least one R_(a1) is O—(CH₂)₁₄—NR_(n1)R_(n2) orNH—(CH₂)₁₋₄—NR_(n1)R_(n2), wherein R_(n1) and R_(n2) are eachindependently C₁-C₄ alkyl (e.g., methyl, ethyl, n-propyl, i-propyl,n-butyl, i-butyl, s-butyl, or t-butyl).

(d20) In one embodiment, X, p3, R_(a1)′, and R₂ are each as defined,where applicable, in any of (d1), (d2), (d4)-(d14), (d17), and (d18),and at least one R_(a1) is O—(CH₂)₁₋₄—NR_(n1)R_(n2) orNH—(CH₂)₁₋₄—NR_(n1)R_(n2), wherein R_(n1) and R_(n2), together with thenitrogen atom to which they are bonded, form a 4- to 7-memberedheterocyclyl ring comprising 1 to 3 heteroatoms selected from N, O, andS (e.g., azetidinyl, oxetanyl, oxazetidinyl, diazetidinyl, pyrrolidinyl,tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl,oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl,triazolidinyl, oxadiazolidinyl, isoxadiazolidinyl, thiadiazolidinyl,isothiadiazolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl,hexahydropyridazinyl, hexahydropyrimidinyl, morpholinyl, triazinanyl,azepanyl, oxazepanyl, diazepanyl, etc.) optionally substituted with oneor more C₁-C₆ alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl,i-butyl, s-butyl, t-butyl, pentyl, or hexyl). In a further embodiment,R_(n1) and R_(n2), together with the nitrogen atom to which they arebonded, form a 5- or 6-membered heterocyclyl ring comprising 1 to 3heteroatoms selected from N, O, and S (e.g., pyrrolidinyl,tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl,oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl,triazolidinyl, oxadiazolidinyl, isoxadiazolidinyl, thiadiazolidinyl,isothiadiazolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl,hexahydropyridazinyl, hexahydropyrimidinyl, morpholinyl, triazinanyl,etc.) optionally substituted with one or more C₁-C₆ alkyl (e.g., methyl,ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl,or hexyl). In a further embodiment, R_(n1) and R_(n2), together with thenitrogen atom to which they are bonded, form a pyrrolidinyl orpiperidinyl ring optionally substituted with one or more C₁-C₆ alkyl(e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl,t-butyl, pentyl, or hexyl).

(d21) In one embodiment, in (d19) or (d20), at least one R_(a1) isO—(CH₂)₁₋₄—NR_(n1)R_(n2). In a further embodiment, at least one R_(a1)is O—(CH₂)₁—NR_(n1)R_(n2). In another further embodiment, at least oneR_(a1) is O—(CH₂)₂—NR_(n1)R_(n2).

(d22) In one embodiment, in (d23) or (d24), at least one R_(a1) isNR_(n1)—(CH₂)₁₋₄—NR_(n1)R_(n2). In a further embodiment, at least oneR_(a1) is NR_(n1)—(CH₂)₁—NR_(n1)R_(n2). In another further embodiment,at least one R_(a1) is NR_(n1)—(CH₂)₂—NR_(n1)R_(n2).

(d23) In one embodiment, X, p3, R_(a1)′, and R₂ are each as defined,where applicable, in any of (d1), (d2), (d4)-(d14), (d17), and (d18),and at least one R_(a1) is heterocyclyl comprising one or two 4- to6-membered rings and 1-4 heteroatoms selected from N, O, and Soptionally substituted with one or more R₁₁. In a further embodiment, atleast one R_(a1) is heterocyclyl comprising one 4- to 6-membered ringand 1-4 heteroatoms selected from N, O, and S (e.g., azetidinyl,oxetanyl, oxazetidinyl, diazetidinyl, pyrrolidinyl, tetrahydrofuranyl,tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl,isoxazolidinyl, thiazolidinyl, isothiazolidinyl, triazolidinyl,oxadiazolidinyl, isoxadiazolidinyl, thiadiazolidinyl,isothiadiazolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl,hexahydropyridazinyl, hexahydropyrimidinyl, morpholinyl, triazinanyl,etc.) optionally substituted with one or more R₁₁. In a furtherembodiment, at least one R_(a1) is azetidinyl, pyrrolidinyl,piperidinyl, or piperazinyl optionally substituted with one or more R₁₁.

(d24) In one embodiment, X, p3, R_(a1)′, and R₂ are each as defined,where applicable, in any of (d1), (d2), (d4)-(d14), (d17), and (d18),and at least one R_(a1) is C₁-C₆ straight-chain or C₃-C₆ branched alkyl,including methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl,t-butyl, pentyl, and hexyl. In a further embodiment, at least one R_(a1)is C₁-C₄ alkyl selected from methyl, ethyl, n-propyl, i-propyl, n-butyl,i-butyl, s-butyl, and t-butyl. In a further embodiment, at least oneR_(a1) is methyl.

(d25) In one embodiment, X, p3, R_(a1)′, and R₂ are each as defined,where applicable, in any of (d1), (d2), (d4)-(d14), (d17), and (d18),and at least one R_(a1) is C₁-C₆ straight-chain or C₃-C₆ branchedhaloalkyl, including methyl, ethyl, n-propyl, i-propyl, n-butyl,i-butyl, s-butyl, t-butyl, pentyl, and hexyl, each of which issubstituted with one or more halogen (e.g., F, Cl, Br, or I). In afurther embodiment, at least one R_(a1) is C₁-C₄ haloalkyl selected frommethyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, andt-butyl, each of which is substituted with one or more halogen (e.g., F,Cl, Br, or I). In a further embodiment, at least one R_(a1) is CH₂F,CHF₂, or CF₃.

(d26) In one embodiment, X, p3, R_(a1)′, and R₂ are each as defined,where applicable, in any of (d1), (d2), (d4)-(d14), (d17), and (d18),and at least one R_(a1) is C₁-C₆ straight-chain or C₃-C₆ branchedalkoxy, including methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy,i-butoxy, s-butoxy, t-butoxy, pentoxy, and hexyloxy. In a furtherembodiment, at least one R_(a1) is C₁-C₄ alkoxy selected from methoxy,ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, andt-butoxy. In a further embodiment, at least one R_(a1) is methoxy orethoxy.

(d27) In one embodiment, X, p3, R_(a1)′, and R₂ are each as defined,where applicable, in any of (d1), (d2), (d4)-(d14), (d17), and (d18),and at least one R_(a1) is C₁-C₆ straight-chain or C₃-C₆ branchedhaloalkoxy, including methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy,i-butoxy, s-butoxy, t-butoxy, pentoxy, and hexyloxy, each of which issubstituted with one or more halogen (e.g., F, Cl, Br, or I). In afurther embodiment, at least one R_(a1) is C₁-C₄ haloalkoxy selectedmethoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, andt-butoxy, each of which is substituted with one or more halogen (e.g.,F, Cl, Br, or I). In a further embodiment, at least one R_(a1) is OCH₂F,OCHF₂, or OCF₃.

(d28) In one embodiment, X, p3, R_(a1)′, and R₂ are each as defined,where applicable, in any of (d1), (d2), (d4)-(d14), (d17), and (d18),and at least one R_(a1) is OH.

(d29) In one embodiment, X, p3, R_(a1)′, and R₂ are each as defined,where applicable, in any of (d1), (d2), (d4)-(d14), (d17), and (d18),and at least one R_(a1) is halogen (e.g., F, Cl, Br, or I). In a furtherembodiment, at least one R_(a1) is F or Cl. In a further embodiment, atleast one R_(a1) is F.

In one embodiment, the compound is of Formula Ie1 or Ie2:

or a pharmaceutically acceptable salt thereof, wherein R₂ and R_(a1) areeach as defined herein above in Formula I′ or Formula I.

In one embodiment, each R_(a1) is independently R_(a1a) or R_(a1b),wherein R_(a1a) is C₁-C₆ alkyl (e.g., methyl or ethyl), C₁-C₆ haloalkyl(e.g., CHF₂, CH₂F, or CF₃), C₁-C₆ alkoxy (e.g., OCH₃), C₁-C₆ haloalkoxy(e.g., OCHF₂, OCH₂F, or OCF₃), or halogen (e.g., F or Cl); and R_(a1b)is

In one embodiment, one R_(a1) is R_(a1a), and the other one R_(a1) isR_(a1b).

In one embodiment, R₂ is Q-R₂′, wherein Q is (CH₂)₀₋₃ and R₂′ isheterocyclyl comprising one 4- to 7-membered ring and 1-3 heteroatomsselected from N, O, and S, wherein the heterocyclyl is substituted withone or more R_(b1).

In one embodiment, R₂ is CH₂—R₂′, wherein R₂′ is heterocyclyl comprisingone 4- to 7-membered ring and 1-3 heteroatoms selected from N, O, and S,wherein the heterocyclyl is substituted with one or more R_(b1).

In one embodiment, R₂ is CH₂—R₂′, wherein R₂′ is pyrrolidinyl orpiperidinyl comprising one 4- to 7-membered ring and 1-3 heteroatomsselected from N, O, and S, wherein the pyrrolidinyl or piperidinyl issubstituted with one or more R_(b1).

In one embodiment, R₂ is

In one embodiment, the compound is of Formula Ie3 or Ie4:

or a pharmaceutically acceptable salt thereof.

In one embodiment, R_(a1a) is methyl, ethyl, CHF₂, CH₂F, CF₃, OCH₃,OCHF₂, OCH₂F, OCF₃, F, or Cl; and R_(a1b) is

In one embodiment, R₂ is

Any of the substituents described herein for any of R₂ and R_(a1) can becombined with any of the substituents described herein for one or moreof the remainder of R₂ and R_(a1).

In one embodiment, the compound is of any one of Formulae Xa, Xb, Xc,Xd, and Xe:

or a pharmaceutically acceptable salt thereof.

In one embodiment, R₁ is phenyl substituted with one or more R_(a2); andR₂ is H, NH₂, or C₁-C₄ alkyl. In one embodiment, R₁ is phen substitutedwith one or more R_(a2); and R₂ is H. In one embodiment, R₁ is phenylsubstituted with one or more R_(a2); and R₂ is NH₂. In one embodiment,R₁ is phenyl substituted with one or more R_(a2); and R₂ is C₁-C₄ alkyl.In one embodiment, R₁ is phenyl substituted with one or more R_(a2); andR₂ is methyl.

In one embodiment, R₃ is C₆-C₁₀ aryl optionally substituted with one ormore R₇. In one embodiment, R₃ is C₆-C₁₀ aryl optionally substitutedwith two R₇. In one embodiment, R₃ is C₆-C₁₀ aryl optionally substitutedwith two halogen. In one embodiment, R₃ is C₆-C₁₀ aryl optionallysubstituted with two F.

In one embodiment, R₄ is H. In one embodiment, R₄ is C₁-C₄ alkyl.

In one embodiment, R₅ is H. In one embodiment, R₅ is C₁-C₄ alkyl.

In one embodiment, both of R₄ and R₅ are H.

In one embodiment, R₆ is H. In one embodiment, R₆ is C₁-C₄ alkyl.

In one embodiment, at least one R₇ is halogen. In one embodiment, atleast one R₇ is F.

In one embodiment, at least one R_(a2) is C₁-C₆ alkoxy. In oneembodiment, at least one R_(a2) is methoxy.

In one embodiment, at least one R_(a2) is O—(CH₂)₄—NR_(n1)R_(n2). In oneembodiment, at least one R_(a2) is O—(CH₂)₂—NR_(n1)R_(n2). In oneembodiment, at least one R_(a2) is O—(CH₂)₂—N(CH₃)₂.

In one embodiment, at least one R_(a2) isNR_(n1)—(CH₂)₁₋₄—NR_(n1)R_(n2). In one embodiment, at least one R_(a2)is NR_(n1)—(CH₂)₂—NR_(n1)R_(n2). In one embodiment, at least one R_(a2)is N(CH₃)—(CH₂)₂—N(CH₃)₂.

In one embodiment, at least one R_(a2) is

In one embodiment, at least one R_(a2) is

In one embodiment, at least one W is

In one embodiment, L₃ is —NR_(L3a)—. In one embodiment, R_(L3a) is H.

In one embodiment, R_(E1) is H. In one embodiment, R_(E2) is H. In oneembodiment, R_(E3) is H. In one embodiment, R_(E1), R_(E2), and R_(E3)are each H.

In one embodiment, Y is O.

Any of the substituents described herein for any of R₁, R₂, R₂′, R₃, R₄,R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R_(a1), R_(a2), R_(b1), R_(b2), R_(n1),R_(n2), R_(n3), R_(n4), W, L₃, L₄, R_(L3a), R_(L3b), R_(E1), R_(E2),R_(E3), R_(E4), R_(E5), R_(E6), R_(E7), R_(EE), Y, a, and z, forexample, in any of Formulae X, I, I′, and Xa-Xe, can be combined withany of the substituents described herein for one or more of theremainder of R₁, R₂, R₂′, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R_(a1),R_(a2), R_(b1), R_(b2), R_(n1), R_(n2), R_(n3), R_(n4), W, L₃, L₄,R_(L3a), R_(L3b), R_(E1), R_(E2), R_(E3), R_(E4), R_(E5), R_(E6),R_(E7), R_(EE), Y, a, and z, for example, in any of Formulae X, I, I′,and Xa-Xe.

Non-limiting illustrative compounds of the application are listed inTables 1-6.

In one embodiment, the compound is selected from the compounds disclosedin Tables 1-6 (e.g., Compound Nos. 1-144).

In one embodiment, the compound is selected from the compounds disclosedin Tables 1-5 (e.g., Compound Nos. 1-137).

In one embodiment, the compound is selected from the compounds disclosedin Table 6 (e.g., Compound Nos. 138-144).

TABLE 1 Compound Structure # 1

1b

2

3

4

5

6

7

8

9

10

11

12

13

14

TABLE 2 Compound # Structure 15

16

17

18

19

20

21

22

23

24

25

26

27

28

TABLE 3 Compound # Structure 29

30

31

32

33

34

35

TABLE 4 Compound # Structure 36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

TABLE 5 Com- pound # Structure 80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

TABLE 6 Com - pound # Structure 138

139

140

141

142

143

144

The compounds of the application may inhibit one or more receptors ofthe ErbB receptor tyrosine kinase family. For example, a compound of thepresent application may inhibit EGFR, HER2, HER3, and/or HER4, and/orany mutant thereof. In some embodiments, a compound of the presentapplication inhibits EGFR. In some embodiments, a compound of thepresent application inhibits a mutant EGFR. In some embodiments, acompound of the present application inhibits HER2. In some embodiments,a compound of the present application inhibits a mutant HER2. In someembodiments, a compound of the present application inhibits EGFR andHER2 and/or a mutant thereof.

The compounds of the application are capable of modulating (e.g.,inhibiting or decreasing) the activity of EGFR or a mutant thereofand/or HER2 or a mutant thereof.

In some embodiments, the compounds of the present application arecapable of modulating (e.g., inhibiting or decreasing) the activity ofEGFR containing one or more mutations. In some embodiments, the mutantEGFR contains one or more mutations described herein. In someembodiments, the compounds of the present application are capable ofmodulating (e.g., inhibiting or decreasing) the activity of EGFRcontaining one or more mutations, but do not affect the activity of awild-type EGFR.

In some embodiments, the compounds of the application exhibit greaterinhibition of EGFR containing one or more mutations as described hereinrelative to a wild-type EGFR. In some embodiments, the compounds of theapplication exhibit at least 2-fold, 3-fold, 5-fold, 10-fold, 25-fold,50-fold or 100-fold greater inhibition of EGFR containing one or moremutations as described herein relative to a wild-type EGFR. In someembodiments, the compounds of the application exhibit up to 1000-foldgreater inhibition of EGFR containing one or more mutations as describedherein relative to a wild-type EGFR.

In some embodiments, the compounds of the application exhibit from about2-fold to about 10-fold greater inhibition of EGFR containing one ormore mutations as described herein relative to a wild-type EGFR. In someembodiments, the compounds of the application exhibit from about 10-foldto about 100-fold greater inhibition of EGFR containing one or moremutations as described herein relative to a wild-type EGFR. In someembodiments, the compounds of the application exhibit from about100-fold to about 1000-fold greater inhibition of EGFR containing one ormore mutations as described herein relative to a wild-type EGFR. In someembodiments, the compounds of the application exhibit from about1000-fold to about 10000-fold greater inhibition of EGFR containing oneor more mutations as described herein relative to a wild-type EGFR.

In some embodiments, the compounds of the present application arecapable of modulating (e.g., inhibiting or decreasing) the activity ofHER2 containing one or more mutations. In some embodiments, the mutantHER2 contains one or more mutations described herein. In someembodiments, the compounds of the present application are capable ofmodulating (e.g., inhibiting or decreasing) the activity of HER2containing one or more mutations, but do not affect the activity of awild-type HER2.

In some embodiments, the compounds of the application exhibit greaterinhibition of HER2 containing one or more mutations as described hereinrelative to a wild-type HER2. In some embodiments, the compounds of theapplication exhibit at least 2-fold, 3-fold, 5-fold, 10-fold, 25-fold,50-fold or 100-fold greater inhibition of HER2 containing one or moremutations as described herein relative to a wild-type HER2. In someembodiments, the compounds of the application exhibit up to 1000-foldgreater inhibition of HER2 containing one or more mutations as describedherein relative to a wild-type HER2.

In some embodiments, the compounds of the application exhibit from about2-fold to about 10-fold greater inhibition of HER2 containing one ormore mutations as described herein relative to a wild-type HER2. In someembodiments, the compounds of the application exhibit from about 10-foldto about 100-fold greater inhibition of HER2 containing one or moremutations as described herein relative to a wild-type HER2. In someembodiments, the compounds of the application exhibit from about100-fold to about 1000-fold greater inhibition of HER2 containing one ormore mutations as described herein relative to a wild-type HER2. In someembodiments, the compounds of the application exhibit from about1000-fold to about 10000-fold greater inhibition of HER2 containing oneor more mutations as described herein relative to a wild-type HER2.

In some embodiments, the compounds of the present application arecapable of modulating (e.g., inhibiting or decreasing) the activity ofEGFR containing one or more mutations and HER2 containing one or moremutations. In some embodiments, the mutant EGFR or mutant HER2 containsone or more mutations described herein. In some embodiments, thecompounds of the present application are capable of modulating (e.g.,inhibiting or decreasing) the activity of EGFR containing one or moremutations and HER2 containing one or more mutations, but do not affectthe activity of a wild-type EGFR or a wild-type HER2.

In some embodiments, the compounds of the application exhibit greaterinhibition of EGFR containing one or more mutations and HER2 containingone or more mutations as described herein relative to a wild-type EGFRor a wild-type HER2. In some embodiments, the compounds of theapplication exhibit at least 2-fold, 3-fold, 5-fold, 10-fold, 25-fold,50-fold or 100-fold greater inhibition of EGFR containing one or moremutations and HER2 containing one or more mutations as described hereinrelative to a wild-type EGFR or a wild-type HER2. In some embodiments,the compounds of the application exhibit up to 1000-fold greaterinhibition of EGFR containing one or more mutations and HER2 containingone or more mutations as described herein relative to a wild-type EGFRor a wild-type HER2.

In some embodiments, the compounds of the application exhibit from about2-fold to about 10-fold greater inhibition of EGFR containing one ormore mutations and HER2 containing one or more mutations as describedherein relative to a wild-type EGFR or a wild-type HER2. In someembodiments, the compounds of the application exhibit from about 10-foldto about 100-fold greater inhibition of EGFR containing one or moremutations and HER2 containing one or more mutations as described hereinrelative to a wild-type EGFR or a wild-type HER2. In some embodiments,the compounds of the application exhibit from about 100-fold to about1000-fold greater inhibition of EGFR containing one or more mutationsand HER2 containing one or more mutations as described herein relativeto a wild-type EGFR or a wild-type HER2. In some embodiments, thecompounds of the application exhibit from about 1000-fold to about10000-fold greater inhibition of EGFR containing one or more mutationsand HER2 containing one or more mutations as described herein relativeto a wild-type EGFR or a wild-type HER2.

More potent modulation (e.g., inhibition) of EGFR containing one or moremutations and/or HER2 containing one or more mutations, such as thosedescribed herein, relative to a wild-type EGFR or a wild-type HER2,provides a novel approach to the treatment or prevention of diseasesincluding, but not limited to, cancer and metastasis, inflammation,arthritis, systemic lupus erthematosus, skin-related disorders,pulmonary disorders, cardiovascular disease, ischemia, neurodegenerativedisorders, liver disease, gastrointestinal disorders, viral andbacterial infections, central nervous system disorders, Alzheimer'sdisease, Parkinson's disease, Huntington's disease, amyotrophic lateralsclerosis, spinal cord injury, and peripheral neuropathy.

In some embodiments, the inhibition of activity of EGFR or HER2 or amutant thereof is measured by IC₅₀.

In some embodiments, the inhibition of activity of EGFR or HER2 or amutant thereof is measured by EC₅₀.

In some embodiments, the compounds of the application are potentinhibitor of a drug-resistant EGFR mutant relative to a wild-type EGFR.In some embodiments, the compounds of the application are more potentthan one or more known EGFR inhibitors, including but not limited togefitinib, erlotinib, lapatinib, afatinib, dacomitinib, osimertinib,neratinib, canertinib, sapitinib, mubritinib, irbinitinib, WZ4002,CL-387,785, CP-724714, CUDC-101, AEE788, AC480, and TAK-285. In someembodiments, the compounds of the application are at least about 2-fold,3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or about 100-fold more potent(e.g., as measured by IC₅₀) than one or more known EGFR inhibitors,including but not limited to gefitinib, erlotinib, lapatinib, afatinib,dacomitinib, osimertinib, neratinib, canertinib, sapitinib, mubritinib,irbinitinib, WZ4002, CL-387,785, CP-724714, CUDC-101, AEE788, AC480, andTAK-285.

In some embodiments, the compounds of the application are potentinhibitor of a drug-resistant HER2 mutant relative to a wild-type HER2.In some embodiments, the compounds of the application are more potentthan one or more known HER2 inhibitors, including but not limited togefitinib, erlotinib, lapatinib, afatinib, dacomitinib, osimertinib,neratinib, canertinib, sapitinib, mubritinib, irbinitinib, WZ4002,CL-387,785, CP-724714, CUDC-101, AEE788, AC480, TAK-285, poziotinib, andpyrotinib. In some embodiments, the compounds of the application are atleast about 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold or about100-fold more potent (e.g., as measured by IC₅₀) than one or more knownHER2 inhibitors, including but not limited to gefitinib, erlotinib,lapatinib, afatinib, dacomitinib, osimertinib, neratinib, canertinib,sapitinib, mubritinib, irbinitinib, WZ4002, CL-387,785, CP-724714,CUDC-101, AEE788, AC480, TAK-285, poziotinib, and pyrotinib.

In some embodiments, the compounds of the application are potentinhibitor of a drug-resistant EGFR mutant and drug-resistant HER2 mutantrelative to a wild-type EGFR and a wild-type HER2. In some embodiments,the compounds of the application are more potent than one or more knownEGRF and/or HER2 inhibitors, including but not limited to gefitinib,erlotinib, lapatinib, afatinib, dacomitinib, osimertinib, neratinib,canertinib, sapitinib, mubritinib, irbinitinib, WZ4002, CL-387,785,CP-724714, CUDC-101, AEE788, AC480, TAK-285, poziotinib, and pyrotinib.In some embodiments, the compounds of the application are at least about2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold or about 100-fold morepotent (e.g., as measured by IC₅₀) than one or more known EGRF and/orHER2 inhibitors, including but not limited to gefitinib, erlotinib,lapatinib, afatinib, dacomitinib, osimertinib, neratinib, canertinib,sapitinib, mubritinib, irbinitinib, WZ4002, CL-387,785, CP-724714,CUDC-101, AEE788, AC480, TAK-285, poziotinib, and pyrotinib.

Potency of a compound can be determined by IC₅₀ value. A compound with alower IC₅₀ value, as determined under substantially similar conditions,is a more potent inhibitor relative to a compound with a higher IC₅₀value. In some embodiments, the substantially similar conditionscomprise determining an EGFR-dependent or a HER2-dependentphosphorylation level in cells expressing a wild-type EGFR, a wild-typeHER2, or a mutant thereof, such as those described herein, or a fragmentof any thereof.

The selectivity between wild-type EGFR and EGFR containing one or moremutations as described herein or between wild-type HER2 and HER2containing one or more mutations as described herein can be measuredusing cellular proliferation assays where cell proliferation isdependent on kinase activity. For example, Ba/F3 cells transfected withwild-type EGFR, or Ba/F3 cells transfected with a mutant EGFR can beused. Proliferation assays are performed at a range of inhibitorconcentrations (10 μM, 3 μM, 1.1 μM, 330 nM, 110 nM, 33 nM, 11 nM, 3 nM,I nM) and an EC₅₀ is calculated.

An alternative method to measure effects on EGFR and/or HER2 activity isto assay phosphorylation of wild-type EGFR, wild-type HER2, and/or amutant thereof, such as those described herein. Wild-type EGFR,wild-type HER2, or a mutant thereof, such as those described herein, canbe transfected into cells which do not normally express endogenous EGFRor HER2. The ability of the inhibitor (using concentrations as above) toinhibit phosphorylation can be assayed.

Another aspect of this application is an isotopically labeled compoundof any of the compounds disclosed herein. Such compounds have one ormore isotope atoms which may or may not be radioactive (e.g., ³H, ²H,¹⁴C, ¹³C, ¹⁸F, ³⁵S, ³²P, ¹²⁵I, and ¹³¹I) introduced into the compound.Such compounds are useful for drug metabolism studies and diagnostics,as well as therapeutic applications.

Definitions

Listed below are definitions of various terms used to describe thisapplication. These definitions apply to the terms as they are usedthroughout this specification and claims, unless otherwise limited inspecific instances, either individually or as part of a larger group.

The term “alkyl,” as used herein, refers to saturated, straight- orbranched-chain hydrocarbon radicals containing. In some embodiments,between one and six, or one and eight carbon atoms, respectively.Examples of C₁-C₆ alkyl radicals include, but are not limited to,methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl,n-hexyl radicals; and examples of C₁-C₈ alkyl radicals include, but arenot limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl,neopentyl, n-hexyl, heptyl, octyl radicals.

The term “alkenyl,” as used herein, denotes a monovalent group derivedfrom a hydrocarbon moiety containing. In some embodiments, from two tosix, or two to eight carbon atoms having at least one carbon-carbondouble bond. The double bond may or may not be the point of attachmentto another group. Alkenyl groups include, but are not limited to, forexample, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, heptenyl,octenyl and the like.

The term “alkynyl,” as used herein, denotes a monovalent group derivedfrom a hydrocarbon moiety containing. In some embodiments, from two tosix, or two to eight carbon atoms having at least one carbon-carbontriple bond. The triple bond may or may not be the point of attachmentto another group. Alkynyl groups include, but are not limited to, forexample, ethynyl, propynyl, butynyl, 1-methyl-2-butyn-1-yl, heptynyl,octynyl and the like.

The term “alkoxy” refers to an —O-alkyl radical.

The term “aryl,” as used herein, refers to a mono- or poly-cycliccarbocyclic ring system having one or more aromatic rings, fused ornon-fused, including, but not limited to, phenyl, naphthyl,tetrahydronaphthyl, indanyl, indenyl and the like.

The term “heteroaryl,” as used herein, refers to a mono- or poly-cyclic(e.g., bi-, or tri-cyclic or more) fused or non-fused, radical or ringsystem having at least one aromatic ring, having from five to ten ringatoms of which at least one ring atom is selected from S, O, and N;zero, one, or two ring atoms are additional heteroatoms independentlyselected from S, O, and N; and the remaining ring atoms are carbon.Heteroaryl includes, but is not limited to, pyridinyl, pyrazinyl,pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl,isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl,isoquinolinyl, benzimidazolyl, benzooxazolyl, quinoxalinyl, and thelike.

In accordance with the application, any of the heteroaryls andsubstituted heteroaryls described herein, can be any aromatic group.Aromatic groups can be substituted or unsubstituted.

The term “cycloalkyl” or “carbocyclyl” as used herein, denotes amonovalent group derived from a monocyclic or polycyclic saturated orpartially unsaturated carbocyclic ring compound. Examples ofC₃-C₈-cycloalkyl include, but not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cyclopentyl and cyclooctyl; and examples ofC₃-C₁₂-cycloalkyl include, but not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, bicyclo [2.2.1] heptyl, and bicyclo [2.2.2]octyl. Also contemplated is a monovalent group derived from a monocyclicor polycyclic carbocyclic ring compound having at least onecarbon-carbon double bond by the removal of a single hydrogen atom.Examples of such groups include, but are not limited to, cyclopropenyl,cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl,and the like.

The term “heterocyclyl,” as used herein, refers to a non-aromatic 3-,4-, 5-, 6- or 7-membered ring or a bi- or tri-cyclic group fused ofnon-fused system, where (i) each ring contains between one and threeheteroatoms independently selected from oxygen, sulfur and nitrogen,(ii) each 5-membered ring has 0 to 1 double bonds and each 6-memberedring has 0 to 2 double bonds, (iii) the nitrogen and sulfur heteroatomsmay optionally be oxidized, and (iv) the nitrogen heteroatom mayoptionally be quaternized. Representative heterocyclyl groups include,but are not limited to, [1,3]dioxolane, pyrrolidinyl, pyrazolinyl,pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl,oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl,isothiazolidinyl, and tetrahydrofuryl.

The term “alkylamino” refers to a group having the structure NH(C₁-C₁₂alkyl), e.g., NH(C₁-C₆ alkyl), where C₁-C₆ alkyl is as previouslydefined.

The term “dialkylamino” refers to a group having the structure N(C₁-C₁₂alkyl)₂, e.g., N(C₁-C₆ alkyl)₂, where C₁-C₆ alkyl is as previouslydefined.

The terms “hal,” “halo,” and “halogen,” as used herein, refer to an atomselected from fluorine, chlorine, bromine, and iodine.

As described herein, a compound of the application may optionally besubstituted with one or more substituents, such as are illustratedgenerally above, or as exemplified by particular classes, subclasses,and species of the application. It will be appreciated that the phrase“optionally substituted” is used interchangeably with the phrase“substituted or unsubstituted.” In general, the term “substituted”,whether preceded by the term “optionally” or not, refers to thereplacement of hydrogen in a given structure with the radical of aspecified substituent. Unless otherwise indicated, an optionallysubstituted group may have a substituent at each substitutable positionof the group, and when more than one position in any given structure maybe substituted with more than one substituent selected from a specifiedgroup, and the substituent may be either the same or different at everyposition.

It is understood that the alkyl, alkenyl, alkoxy, aryl, heteroaryl,cycloalkyl, or heterocyclyl, or the like can be substituted, byindependent replacement of one, two, or three or more of the hydrogenatoms thereon with substituents including, but not limited to:

—F, —C₁, —Br, —I, —OH, protected hydroxy, —NO₂, —CN, —NH₂, protectedamino, —NH—C₁-C₁₂-alkyl, —NH—C₂-C₁₂-alkenyl, —NH—C₂-C₁₂-alkenyl,—NH—C₃-C₁₂-cycloalkyl, —NH-aryl, —NH-heteroaryl, —NH-heterocycloalkyl,-dialkylamino, -diarylamino, -diheteroarylamino, —O—C₁-C₁₂-alkyl,—O—C₂-C₁₂-alkenyl, —O—C₂-C₁₂-alkenyl, —O—C3-C₁₂-cycloalkyl, —O-aryl,—O-heteroaryl, —O-heterocycloalkyl, —C(O)—C₁-C₁₂-alkyl,—C(O)—C₂-C₁₂-alkenyl, —C(O)—C₂-C₁₂-alkenyl, —C(O)—C₃-C₁₂-cycloalkyl,—C(O)-aryl, —C(O)— heteroaryl, —C(O)-heterocycloalkyl, —CONH₂,—CONH—C₁-C₁₂-alkyl, —CONH—C₂-C₁₂-alkenyl, —CONH—C₂-C₁₂-alkenyl,—CONH—C₃-C₁₂-cycloalkyl, —CONH-aryl, —CONH-heteroaryl,—CONH-heterocycloalkyl, —OCO₂—C₁-C₁₂-alkyl, —OCO₂—C₂-C₁₂-alkenyl,—OCO₂—C₂-C₁₂-alkenyl, —OCO₂—C₃-C₁₂-cycloalkyl, —OCO₂-aryl,—OCO₂-heteroaryl, —OCO₂-heterocycloalkyl, —OCONH₂, —OCONH—C₁-C₁₂-alkyl,—OCONH— C₂-C₁₂-alkenyl, —OCONH— C₂-C₁₂-alkenyl,—OCONH—C₃-C₁₂-cycloalkyl, —OCONH-aryl, —OCONH-heteroaryl, —OCONH—heterocycloalkyl, —NHC(O)—C₁-C₁₂-alkyl, —NH—C(O)—C₂-C₁₂-alkenyl,—NHC(O)—C₂-C₁₂-alkenyl, —NHC(O)—C₃-C₁₂-cycloalkyl, —NHC(O)-aryl,—NHC(O)-heteroaryl, —NHC(O)-heterocycloalkyl, —NHCO₂—C₁-C₁₂-alkyl,—NHCO₂—C₂-C₁₂-alkenyl, —NHCO₂—C₂-C₁₂-alkenyl, —NHCO₂—C₃-C₁₂-cycloalkyl,—NHCO₂-aryl, —NHCO₂-heteroaryl, —NHCO₂-heterocycloalkyl, NHC(O)NH₂,—NHC(O)NH—C₁-C₁₂-alkyl, —NHC(O)NH—C₂-C₁₂-alkenyl,—NHC(O)NH—C₂-C₁₂-alkenyl, —NHC(O)NH—C₃-C₁₂-cycloalkyl, —NHC(O)NH-aryl,—NHC(O)NH-heteroaryl, NHC(O)NH-heterocycloalkyl, —NHC(S)NH₂,—NHC(S)NH—C₃-C₁₂-alkyl, —NHC(S)NH—C₂-C₁₂-alkenyl,—NHC(S)NH—C₂-C₁₂-alkenyl, —NHC(S)NH—C₃-C₁₂-cycloalkyl, —NHC(S)NH-aryl,—NHC(S)NH-heteroaryl, —NHC(S)NH— heterocycloalkyl, —NHC(NH)NH₂,—NHC(NH)NH—C₁-C₁₂-alkyl, —NHC(NH)NH—C₂-C₁₂-alkenyl,—NH—C(NH)NH—C₂-C₁₂-alkenyl, —NH—C(NH)NH—C₃-C₁₂-cycloalkyl,—NHC(NH)NH-aryl, —NHC(NH)NH-heteroaryl, —NHC(NH)NH-heterocycloalkyl,—NHC(NH)—C₁-C₁₂-alkyl, —NHC(NH)—C₂-C₁₂-alkenyl, —NHC(NH)—C₂-C₁₂-alkenyl,—NHC(NH)—C₃-C₁₂-cycloalkyl, —NHC(NH)-aryl, —NHC(NH)-heteroaryl,—NHC(NH)-heterocycloalkyl, —C(NH)NH—C₁-C₁₂-alkyl,—C(NH)NH—C₂-C₁₂-alkenyl, —C(NH)NH—C₂-C₁₂-alkenyl,C(NH)NH—C₃-C₁₂-cycloalkyl, —C(NH)NH-aryl, —C(NH)NH-heteroaryl,—C(NH)NHheterocycloalkyl, —S(O)—C₁-C₁₂-alkyl, —S(O)—C₂-C₁₂-alkenyl,—S(O)—C₂-C₁₂-alkenyl, —S(O)—C₃-C₁₂-cycloalkyl, —S(O)-aryl,—S(O)-heteroaryl, —S(O)-heterocycloalkyl —SO₂NH₂, —SO₂NH—C₁-C₁₂-alkyl,—SO₂NH—C₂-C₁₂-alkenyl, —SO₂NH—C₂-C₁₂-alkenyl, —SO₂NH—C₃-C₁₂-cycloalkyl,—SO₂NH-aryl, —SO₂NH-heteroaryl, —SO₂NH-heterocycloalkyl,—NHSO₂—C₁-C₁₂-alkyl, —NHSO₂—C₂-C₁₂-alkenyl, —NHSO₂—C₂-C₁₂-alkenyl,—NHSO₂—C₃-C₁₂-cycloalkyl, —NHSO₂-aryl, —NHSO₂-heteroaryl,—NHSO₂-heterocycloalkyl, —CH₂NH₂, —CH₂SO₂CH₃, -aryl, -arylalkyl,-heteroaryl, -heteroarylalkyl,-heterocycloalkyl, —C₃-C₁₂-cycloalkyl,polyalkoxyalkyl, polyalkoxy, -methoxymethoxy,-methoxyethoxy, —SH,—S—C₁-C₁₂-alkyl, —S—C₂-C₁₂-alkenyl, —S—C₂-C₁₂-alkenyl,—S—C₃-C₁₂-cycloalkyl, —S-aryl, —S-heteroaryl, —S-heterocycloalkyl, ormethylthiomethyl.

In some embodiments, the substituent present on a nitrogen atom is anitrogen protecting group (also referred to as an amino protectinggroup). Nitrogen protecting groups include, but are not limited to, —OH,—OR, —N(R)₂, —C(═O)R, —C(═O)N(R)₂, —CO₂R, —SO₂R, —C(═NR)R, —C(═NR)OR,—C(═NR)N(R)₂, —SO₂N(R)₂, —SO₂R, —SO₂OR, —SOR, —C(═S)N(R)₂, —C(═O)SR,—C(═S)SR, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl,3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroarylgroups, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl,aryl, and heteroaryl is independently substituted. Nitrogen protectinggroups are well known in the art and include those described in detailin Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M.Wuts, 3^(rd) edition, John Wiley & Sons, 1999, incorporated herein byreference.

For example, nitrogen protecting groups such as amide groups (e.g.,—C(═O)R) include, but are not limited to, formamide, acetamide,chloroacetamide, trichloroacetamide, trifluoroacetamide,phenylacetamide, 3-phenylpropanamide, picolinamide,3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide,p-phenylbenzamide, o-nitophenylacetamide, o-nitrophenoxyacetamide,acetoacetamide, (N′-dithiobenzyloxyacylamino)acetamide,3-(p-hydroxyphenyl)propanamide, 3-o-nitrophenyl)propanamide,2-methyl-2-(o-nitrophenoxy)propanamide,2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide,3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethioninederivative, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

Nitrogen protecting groups, such as carbamate groups (e.g., —C(═O)OR),include, but are not limited to, methyl carbamate, ethyl carbamante,9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethylcarbamate, 9-(2,7-dibromo)fluorenylmethyl carbamate,2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methylcarbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc),2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate(Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethylcarbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate,1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC),1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC),1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc),1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2′- and4′-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethylcarbamate, t-butyl carbamate (BOC), 1-adamantyl carbamate (Adoc), vinylcarbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate(Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc),8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithiocarbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz),p-nitobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzylcarbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzylcarbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate,2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate,2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methylcarbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc),2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate(Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc),1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate,p-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate,2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc), m-nitrophenylcarbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate,3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methylcarbamate, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzylcarbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentylcarbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate,2,2-dimethoxyacylvinyl carbamate, o-(N,N-dimethylcarboxamido)benzylcarbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate,1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate,2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynl carbamate,isobutyl carbamate, isonicotinyl carbamate,p-(p′-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate,1-methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate,1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate,1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethylcarbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate,p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate,4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzylcarbamate.

Nitrogen protecting groups, such as sulfonamide groups (e.g., —S(═O)₂R),include, but are not limited to, p-toluenesulfonamide (Ts),benzenesulfonamide, 2,3,6,-trimethyl-4-methoxybenzenesulfonamide (Mtr),2,4,6-trimethoxybenzenesulfonamide (Mtb),2,6-dimethyl-4-methoxybenzenesulfonamide (Pme),2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte),4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide(Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds),2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide(Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide,4-(4′,8′-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS),benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

Other nitrogen protecting groups include, but are not limited to,phenothiazinyl-(10)-acyl derivative, N′-p-toluenesulfonylaminoacylderivative, N′-phenylaminothioacyl derivative, N-benzoylphenylalanylderivative, N-acetylmethionine derivative,4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts),N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole,N-1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE),5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted3,5-dinitro-4-pyridone, N-methylamine, N-allylamine,N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxy propylamine,N-(1-isopropyl-4-nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary ammoniumsalts, N-benzylamine, N-di(4-methoxyphenyl)methylamine,N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr),N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr),N-9-phenylfluorenylamine (PhF),N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm),N-2-picolylamino N′-oxide, N-1,1-dimethylthiomethyleneamine,N-benzylideneamine, N-p-methoxybenzylideneamine,N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine,N—(N′,N′-dimethylaminomethylene)amine, N,N′-isopropylidenediamine,N-p-nitrobenzylideneamine, N-salicylideneamine,N-5-chlorosalicylideneamine,N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine,N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine,N-borane derivative, N-diphenylborinic acid derivative,N-[phenyl(pentaacylchromium- or tungsten)acyl]amine, N-copper chelate,N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-oxide,diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt),diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzylphosphoramidate, diphenyl phosphoramidate, benzenesulfenamide,o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide,pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide,triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys).

As used herein, a “leaving group” (LG) is an art-understood termreferring to a molecular fragment that departs with a pair of electronsin heterolytic bond cleavage, wherein the molecular fragment is an anionor neutral molecule. As used herein, a leaving group can be an atom or agroup capable of being displaced by a nucleophile. See, for example,Smith, March's Advanced Organic Chemistry 6th ed. (501-502). Exemplaryleaving groups include, but are not limited to, halo (e.g., chloro,bromo, iodo) and activated substituted hydroxyl groups (e.g., —OC(═O)SR,—OC(═O)R, —OCO₂R, —OC(═O)N(R)₂, —OC(═NR)R, —OC(═NR)OR, —OC(═NR)N(R)₂,—OS(═O)R, —OSO₂R, —OP(R)₂, —OP(R)₃, —OP(═O)₂R, —OP(═O)R)₂, —OP(═O)(OR)₂,—OP(═O)₂N(R)₂, and —OP(═O)(NR)₂). Examples of suitable leaving groupsinclude, but are not limited to, halogen (such as F, Cl, Br, or I(iodine)), alkoxycarbonyloxy, aryloxycarbonyloxy, alkanesulfonyloxy,arenesulfonyloxy, alkyl-carbonyloxy (e.g., acetoxy), arylcarbonyloxy,aryloxy, methoxy, N,O-dimethylhydroxylamino, pixyl, and haloformates. Insome cases, the leaving group is a sulfonic acid ester, such astoluenesulfonate (tosylate, -OTs), methanesulfonate (mesylate, -OMs),p-bromobenzenesulfonyloxy (brosylate, -OBs), ortrifluoromethanesulfonate (triflate, -OTf). In some cases, the leavinggroup is a brosylate, such as p-bromobenzenesulfonyloxy. In some cases,the leaving group is a nosylate, such as 2-nitrobenzenesulfonyloxy. Insome embodiments, the leaving group is a sulfonate-containing group. Insome embodiments, the leaving group is a tosylate group. The leavinggroup may also be a phosphineoxide (e.g., formed during a Mitsunobureaction) or an internal leaving group such as an epoxide or cyclicsulfate. Other non-limiting examples of leaving groups are water,ammonia, alcohols, ether moieties, thioether moieties, zinc halides,magnesium moieties, diazonium salts, and copper moieties.

The term “cancer” includes, but is not limited to, the followingcancers: epidermoid Oral: buccal cavity, lip, tongue, mouth, pharynx;Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma,liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; Lung:bronchogenic carcinoma (squamous cell or epidermoid, undifferentiatedsmall cell, undifferentiated large cell, adenocarcinoma), alveolar(bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma,chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus(squamous cell carcinoma, larynx, adenocarcinoma, leiomyosarcoma,lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas(ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoidtumors, vipoma), small bowel or small intestines (adenocarcinoma,lymphoma, carcinoid tumors, Karposi's sarcoma, leiomyoma, hemangioma,lipoma, neurofibroma, fibroma), large bowel or large intestines(adenocarcinoma, tubular adenoma, villous adenoma, hamartoma,leiomyoma), colon, colon-rectum, colorectal, rectum; Genitourinarytract: kidney (adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma,leukemia), bladder and urethra (squamous cell carcinoma, transitionalcell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma),testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma,choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma,fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma(hepatocellular carcinoma), cholangiocarcinoma hepatoblastoma,angiosarcoma, hepatocellular adenoma, hemangioma, biliary passages;Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibroushistiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma(reticulum cell sarcoma), multiple myeloma, malignant giant cell tumorchordoma, osteochronfroma (osteocartilaginous exostoses), benignchondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma andgiant cell tumors; Nervous system: skull (osteoma, hemangioma,granuloma, xanthoma, osteitis deformans), meninges (meningioma,meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma,glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform,oligodendroglioma, schwannoma, retinoblastoma, congenital tumors),spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological:uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumorcervical dysplasia), ovaries (ovarian carcinoma (serouscystadenocarcinoma, mucinous cystadenocarcinoma, unclassifiedcarcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors,dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma,intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma),vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma(embryonal rhabdomyosarcoma), fallopian tubes (carcinoma), breast;Hematologic: blood (myeloid leukemia (acute and chronic), acutelymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferativediseases, multiple myeloma, myelodysplastic syndrome), Hodgkin'sdisease, non-Hodgkin's lymphoma (malignant lymphoma) hairy cell;lymphoid disorders; Skin: malignant melanoma, basal cell carcinoma,squamous cell carcinoma, Karposi's sarcoma, keratoacanthoma, molesdysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis,Thyroid gland: papillary thyroid carcinoma, follicular thyroidcarcinoma; medullary thyroid carcinoma, undifferentiated thyroid cancer,multiple endocrine neoplasia type 2A, multiple endocrine neoplasia type2B, familial medullary thyroid cancer, pheochromocytoma, paraganglioma;and Adrenal glands; neuroblastoma. Thus, the term “cancerous cell” asprovided herein, includes a cell afflicted by any one of theabove-identified conditions.

WZ4002 refers to a compound of the following structure:

AZD9291, or osimertinib, refers to a compound of the followingstructure:

CL-387,785 refers to a compound of the following structure:

CP-724714 refers to a compound of the following structure:

CUDC-101 refers to a compound of the following structure:

AEE788 refers to a compound of the following structure:

AC480 refers to a compound of the following structure:

TAK-285 refers to a compound of the following structure:

The term “EGFR” herein refers to epidermal growth factor receptorkinase.

The term “HER2”, “Her2”, “ERBB2”, or “Erbb2” herein refers to humanepidermal growth factor receptor 2, HER2 is also known as CD340 or Neu.

As used herein, the term “mutant EGFR” or “EGFR mutant” refers to EGFRwith one or more mutations. In some embodiments, the EGFR mutant has oneor more mutations of exon 18, exon 19 (e.g., exon 19 deletion or exon 19insertion), exon 20 (e.g., exon 20 insertion), and/or exon 21.

In some embodiments, the mutant EGFR contains one or more mutationsselected from an exon 19 deletion (Del 19), an exon 20 insertion (Ins20), L718Q, G719S, G719C, G719A, D761Y, T790M, C797S, L844V, T854A,L858R, L861Q, I941R, V948R, D770delinsGY, D770_N771insSVD,V769_D770insASV, Y764_V765insHH, H773dupH, D770_N771insNPG,H773_V774insNPH, P772_H773insPNP, N771_P772insH, A775_G776insYVMA,A763_Y764insFQEA, V774_C₇₇₅insHV, N771_P772insV, D770_N771insGL,N771delinsGY, and H773_V774insAH. In some embodiments, the mutant EGFRcontains one or more mutations selected from D770delinsGY,D770_N771insSVD, V769_D770insASV, Y764_V765insHH, H773dupH,D770_N771insNPG, H773_V774insNPH, P772_H773insPNP, and N771_P772insH.

In some embodiments, the mutant EGFR contains a combination of two ormore mutations (such as mutations described herein). In someembodiments, the mutant EGFR contains a combination of two or moremutations selected from Del 19/L718Q, Del 19/T790M, Del 19/L844V, Del19/T7901M′L718Q, Del/T790M/C797S, Del 19/T790M/L844V, L858R/L718Q,L858R/L844V, L858R/T790M, L858R/T790M/L718Q, L858R/T790M/C797S, andL858R/T790M/1941R.

An EGFR sensitizing mutation comprises without limitation G719S, G719C,G719A, L861Q, L858R, Del 19, and/or Ins 20. A drug-resistant EGFR mutantcan have without limitation a drug resistance mutation comprising L718Q,D761Y, T790M, T854A, D770delinsGY, D770_N771insSVD, V769_D770insASV,Y764_V765insHH, A775_G776insYVMA, and/or H773dupH.

As used herein, the term “mutant HER2” or “HER2 mutant” refers to HER2with one or more mutations. In some embodiments, the HER2 mutant has oneor more mutations of exon 18, exon 19 (e.g., exon 19 deletion or exon 19insertion), exon 20 (e.g., exon 20 insertion), and/or exon 21.

In some embodiments, the mutant HER2 contains one or more mutationsselected from an exon 19 deletion (Del 19), an exon 20 insertion (Ins20), T798M, T7981, L869R, A775_G776insYVMA, A775_G776insSVMA,A775_G776insI, G776delinsVC, G776delinsLC, P780_Y781insGSP,M774delinsWLV, and G778_S779insCPG. In some embodiments, the mutant EGFRcontains a combination of two or more mutations (such as mutationsdescribed herein).

The term “subject” as used herein refers to a mammal. A subjecttherefore refers to, for example, dogs, cats, horses, cows, pigs, guineapigs, and the like. Preferably the subject is a human. When the subjectis a human, the subject may be referred to herein as a patient.

“Treat”, “treating”, and “treatment” refer to a method of alleviating orabating a disease and/or its attendant symptoms.

“Prevent”, “preventing”, and “prevention” describes reducing oreliminating the onset of a disease, condition, or disorder and/orsymptoms or complications thereof.

The terms “disease(s)”, “disorder(s)”, and “condition(s)” are usedinterchangeably, unless the context clearly dictates otherwise.

The term “therapeutically effective amount” or “effective amount” of acompound or pharmaceutical composition of the application, as usedherein, means a sufficient amount of the compound or pharmaceuticalcomposition so as to decrease the symptoms of a disorder in a subject.As is well understood in the medical arts a therapeutically effectiveamount of a compound or pharmaceutical composition of this applicationwill be at a reasonable benefit/risk ratio applicable to any medicaltreatment. It will be understood, however, that the total daily usage ofthe compounds and compositions of the present application will bedecided by the attending physician within the scope of sound medicaljudgment. The specific inhibitory dose for any particular patient willdepend upon a variety of factors including the disorder being treatedand the severity of the disorder; the activity of the specific compoundemployed; the specific composition employed; the age, body weight,general health, sex and diet of the patient; the time of administration,route of administration, and rate of excretion of the specific compoundemployed; the duration of the treatment; drugs used in combination orcoincidental with the specific compound employed; and like factors wellknown in the medical arts.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts of the compounds formed by the process of the presentapplication which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge, etal. describes pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 66: 1-19 (1977). The salts can be prepared insitu during the final isolation and purification of the compounds of theapplication, or separately by reacting the free base or acid functionwith a suitable acid or base.

Examples of pharmaceutically acceptable salts include, but are notlimited to, nontoxic acid addition salts: salts formed with inorganicacids such as hydrochloric acid, hydrobromic acid, phosphoric acid,sulfuric acid and perchloric acid, or with organic acids such as aceticacid, maleic acid, tartaric acid, citric acid, succinic acid or malonicacid. Other pharmaceutically acceptable salts include, but are notlimited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate,benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate,citrate, cyclopentanepropionate, digluconate, dodecylsulfate,ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate,gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Representative alkali or alkaline earth metal salts includesodium, lithium, potassium, calcium, magnesium, and the like. Furtherpharmaceutically acceptable salts include, when appropriate, nontoxicammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and arylsulfonate.

As used herein, the term “pharmaceutically acceptable ester” refers toesters of the compounds formed by the process of the present applicationwhich hydrolyze in vivo and include those that break down readily in thehuman body to leave the parent compound or a salt thereof. Suitableester groups include, for example, those derived from pharmaceuticallyacceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic,cycloalkanoic and alkanedioic acids, in which each alkyl or alkenylmoiety advantageously has not more than 6 carbon atoms. Examples ofparticular esters include, but are not limited to, formates, acetates,propionates, butyrates, acrylates and ethylsuccinates.

The term “pharmaceutically acceptable prodrugs” as used herein, refersto those prodrugs of the compounds formed by the process of the presentapplication which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswith undue toxicity, irritation, allergic response, and the like,commensurate with a reasonable benefit/risk ratio, and effective fortheir intended use, as well as the zwitterionic forms, where possible,of the compounds of the present application. “Prodrug”, as used herein,means a compound which is convertible in vivo by metabolic means (e.g.,by hydrolysis) to afford any compound delineated by the formulae of theinstant application. Various forms of prodrugs are known in the art, forexample, as discussed in Bundgaard, (ed.), Design of Prodrugs, Elsevier(1985); Widder, et al. (ed.), Methods in Enzymology, vol. 4. AcademicPress (1985); Krogsgaard-Larsen, et al., (ed). “Design and Applicationof Prodrugs, Textbook of Drug Design and Development, Chapter 5, 113-191(1991); Bundgaard, et al., Journal of Drug Deliver Reviews,8:1-38(1992); Bundgaard, J. of Pharmaceutical Sciences, 77:285 et seq.(1988); Higuchi and Stella (eds.) Prodrugs as Novel Drug DeliverySystems, American Chemical Society (1975); and Bernard Testa & JoachimMayer, “Hydrolysis In Drug And Prodrug Metabolism: Chemistry,Biochemistry And Enzymology,” John Wiley and Sons, Ltd. (2002).

This application also encompasses pharmaceutical compositionscontaining, and methods of treating disorders through administering,pharmaceutically acceptable prodrugs of compounds of the application.For example, compounds of the application having free amino, amido,hydroxy or carboxylic groups can be converted into prodrugs. Prodrugsinclude compounds wherein an amino acid residue, or a polypeptide chainof two or more (e.g., two, three or four) amino acid residues iscovalently joined through an amide or ester bond to a free amino,hydroxy or carboxylic acid group of compounds of the application. Theamino acid residues include but are not limited to the 20 naturallyoccurring amino acids commonly designated by three letter symbols andalso includes 4-hydroxyproline, hydroxylysine, demosine, isodemosine,3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid,citrulline, homocysteine, homoserine, ornithine and methionine sulfone.Additional types of prodrugs are also encompassed. For instance, freecarboxyl groups can be derivatized as amides or alkyl esters. Freehydroxy groups may be derivatized using groups including but not limitedto hemisuccinates, phosphate esters, dimethylaminoacetates, andphosphoryloxymethyloxy carbonyls, as outlined in Advanced Drug DeliveryReviews, 1996, 19, 1 15. Carbamate prodrugs of hydroxy and amino groupsare also included, as are carbonate prodrugs, sulfonate esters andsulfate esters of hydroxy groups. Derivatization of hydroxy groups as(acyloxy)methyl and (acyloxy)ethyl ethers wherein the acyl group may bean alkyl ester, optionally substituted with groups including but notlimited to ether, amine and carboxylic acid functionalities, or wherethe acyl group is an amino acid ester as described above, are alsoencompassed. Prodrugs of this type are described in J. Med Chem. 1996,39, 10. Free amines can also be derivatized as amides, sulfonamides orphosphonamides. All of these prodrug moieties may incorporate groupsincluding but not limited to ether, amine and carboxylic acidfunctionalities.

The application also provides for a pharmaceutical compositioncomprising a therapeutically effective amount of a compound of theapplication, or an enantiomer, diastereomer, stereoisomer, orpharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.

In another aspect, the application provides a kit comprising a compoundcapable of inhibiting protein kinase activity of at least one proteinkinase selected from one or more compounds disclosed herein, or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, optionally in combination with asecond agent and instructions for use in treating cancer. In oneembodiment, the compound in the kit inhibits more than one proteinkinase

In another aspect, the application provides a method of synthesizing acompound disclosed herein. The synthesis of the compounds of theapplication can be found herein and in the Examples below. Otherembodiments are a method of making a compound of any of the formulaeherein using any one, or combination of, reactions delineated herein.The method can include the use of one or more intermediates or chemicalreagents delineated herein.

A compound of the application can be prepared as a pharmaceuticallyacceptable acid addition salt by reacting the free base form of thecompound with a pharmaceutically acceptable inorganic or organic acid.Alternatively, a pharmaceutically acceptable base addition salt of acompound of the application can be prepared by reacting the free acidform of the compound with a pharmaceutically acceptable inorganic ororganic base. Alternatively, the salt forms of the compounds of theapplication can be prepared using salts of the starting materials orintermediates.

The free acid or free base forms of the compounds of the application canbe prepared from the corresponding base addition salt or acid additionsalt from, respectively. For example, a compound of the application inan acid addition salt form can be converted to the corresponding freebase by treating with a suitable base (e.g., ammonium hydroxidesolution, sodium hydroxide, and the like). A compound of the applicationin a base addition salt form can be converted to the corresponding freeacid by treating with a suitable acid (e.g., hydrochloric acid, etc.).

Prodrugs of the compounds of the application can be prepared by methodsknown to those of ordinary skill in the art (e.g., for further detailssee Saulnier et al., (1994), Bioorganic and Medicinal Chemistry Letters,Vol. 4, p. 1985). For example, appropriate prodrugs can be prepared byreacting a non-derivatized compound of the application with a suitablecarbamylating agent (e.g., 1,1-acyloxyalkylcarbanochloridate,para-nitrophenyl carbonate, or the like).

Protected derivatives of the compounds of the application can be made bymeans known to those of ordinary skill in the art. A detaileddescription of techniques applicable to the creation of protectinggroups and their removal can be found in T. W. Greene, “ProtectingGroups in Organic Chemistry”, 3rd edition, John Wiley and Sons, Inc.,1999.

Compounds of the present application can be conveniently prepared orformed during the process of the application, as solvates (e.g.,hydrates). Hydrates of compounds of the present application can beconveniently prepared by recrystallization from an aqueous/organicsolvent mixture, using organic solvents such as dioxin, tetrahydrofuranor methanol.

Acids and bases useful in the methods herein are known in the art. Acidcatalysts are any acidic chemical, which can be inorganic (e.g.,hydrochloric, sulfuric, nitric acids, aluminum trichloride) or organic(e.g., camphorsulfonic acid, p-toluenesulfonic acid, acetic acid,ytterbium triflate) in nature. Acids are useful in either catalytic orstoichiometric amounts to facilitate chemical reactions. Bases are anybasic chemical, which can be inorganic (e.g., sodium bicarbonate,potassium hydroxide) or organic (e.g., triethylamine, pyridine) innature. Bases are useful in either catalytic or stoichiometric amountsto facilitate chemical reactions.

Combinations of substituents and variables envisioned by thisapplication are only those that result in the formation of stablecompounds. The term “stable”, as used herein, refers to compounds whichpossess stability sufficient to allow manufacture and which maintainsthe integrity of the compound for a sufficient period of time to beuseful for the purposes detailed herein (e.g., therapeutic orprophylactic administration to a subject).

When any variable (e.g., R₇) occurs more than one time in anyconstituent or formula for a compound, its definition at each occurrenceis independent of its definition at every other occurrence. Thus, forexample, if a group is shown to be substituted with one or more R₇moieties, then R₇ at each occurrence is selected independently from thedefinition of R₇. Also, combinations of substituents and/or variablesare permissible, but only if such combinations result in stablecompounds within a designated atom's normal valency.

In addition, some of the compounds of this application have one or moredouble bonds, or one or more asymmetric centers. Such compounds canoccur as racemates, racemic mixtures, single enantiomers, individualdiastereomers, diastereomeric mixtures, and cis- or trans- or E- orZ-double isomeric forms, and other stereoisomeric forms that may bedefined, in terms of absolute stereochemistry, as (R)- or (S)-, or as(D)- or (L)- for amino acids. When the compounds described hereincontain olefinic double bonds or other centers of geometric asymmetry,and unless specified otherwise, it is intended that the compoundsinclude both E and Z geometric isomers. The configuration of anycarbon-carbon double bond appearing herein is selected for convenienceonly and is not intended to designate a particular configuration unlessthe text so states; thus a carbon-carbon double bond depictedarbitrarily herein as trans may be cis, trans, or a mixture of the twoin any proportion. All such isomeric forms of such compounds areexpressly included in the present application.

Optical isomers may be prepared from their respective optically activeprecursors by the procedures described herein, or by resolving theracemic mixtures. The resolution can be carried out in the presence of aresolving agent, by chromatography or by repeated crystallization or bysome combination of these techniques which are known to those skilled inthe art. Further details regarding resolutions can be found in Jacques,et al., Enantiomers, Racemates, and Resolutions (John Wiley & Sons,1981).

“Isomerism” means compounds that have identical molecular formulae butdiffer in the sequence of bonding of their atoms or in the arrangementof their atoms in space. Isomers that differ in the arrangement of theiratoms in space are termed “stereoisomers”. Stereoisomers that are notmirror images of one another are termed “diastereoisomers”, andstereoisomers that are non-superimposable mirror images of each otherare termed “enantiomers” or sometimes optical isomers. A mixturecontaining equal amounts of individual enantiomeric forms of oppositechirality is termed a “racemic mixture”.

A carbon atom bonded to four non-identical substituents is termed a“chiral center”.

“Chiral isomer” means a compound with at least one chiral center.Compounds with more than one chiral center may exist either as anindividual diastereomer or as a mixture of diastereomers, termed“diastereomeric mixture”. When one chiral center is present, astereoisomer may be characterized by the absolute configuration (R or S)of that chiral center. Absolute configuration refers to the arrangementin space of the substituents attached to the chiral center. Thesubstituents attached to the chiral center under consideration areranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog.(Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahnet al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951(London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem.Educ. 1964, 41, 116).

“Geometric isomer” means the diastereomers that owe their existence tohindered rotation about double bonds. These configurations aredifferentiated in their names by the prefixes cis and trans, or Z and E,which indicate that the groups are on the same or opposite side of thedouble bond in the molecule according to the Cahn-Ingold-Prelog rules.

Furthermore, the structures and other compounds discussed in thisapplication include all atropic isomers thereof “Atropic isomers” are atype of stereoisomer in which the atoms of two isomers are arrangeddifferently in space. Atropic isomers owe their existence to arestricted rotation caused by hindrance of rotation of large groupsabout a central bond. Such atropic isomers typically exist as a mixture,however as a result of recent advances in chromatography techniques; ithas been possible to separate mixtures of two atropic isomers in selectcases.

“Tautomer” is one of two or more structural isomers that exist inequilibrium and is readily converted from one isomeric form to another.This conversion results in the formal migration of a hydrogen atomaccompanied by a switch of adjacent conjugated double bonds. Tautomersexist as a mixture of a tautomeric set in solution. In solid form,usually one tautomer predominates. In solutions where tautomerization ispossible, a chemical equilibrium of the tautomers will be reached. Theexact ratio of the tautomers depends on several factors, includingtemperature, solvent and pH. The concept of tautomers that areinterconvertable by tautomerizations is called tautomerism.

Of the various types of tautomerism that are possible, two are commonlyobserved. In keto-enol tautomerism a simultaneous shift of electrons anda hydrogen atom occurs. Ring-chain tautomerism arises as a result of thealdehyde group (—CHO) in a sugar chain molecule reacting with one of thehydroxy groups (—OH) in the same molecule to give it a cyclic(ring-shaped) form as exhibited by glucose. Common tautomeric pairs are:ketone-enol, amide-nitrile, lactam-lactim, amide-imidic acid tautomerismin heterocyclic rings (e.g., in nucleobases such as guanine, thymine andcytosine), amine-enamine and enamine-enamine. The compounds of thisapplication may also be represented in multiple tautomeric forms, insuch instances, the application expressly includes all tautomeric formsof the compounds described herein (e.g., alkylation of a ring system mayresult in alkylation at multiple sites, the application expresslyincludes all such reaction products).

In the present application, the structural formula of the compoundrepresents a certain isomer for convenience in some cases, but thepresent application includes all isomers, such as geometrical isomers,optical isomers based on an asymmetrical carbon, stereoisomers,tautomers, and the like. In the present specification, the structuralformula of the compound represents a certain isomer for convenience insome cases, but the present application includes all isomers, such asgeometrical isomers, optical isomers based on an asymmetrical carbon,stereoisomers, tautomers, and the like.

Additionally, the compounds of the present application, for example, thesalts of the compounds, can exist in either hydrated or unhydrated (theanhydrous) form or as solvates with other solvent molecules.Non-limiting examples of hydrates include monohydrates, dihydrates, etc.Non-limiting examples of solvates include ethanol solvates, acetonesolvates, etc.

“Solvate” means solvent addition forms that contain eitherstoichiometric or non stoichiometric amounts of solvent. Some compoundshave a tendency to trap a fixed molar ratio of solvent molecules in thecrystalline solid state, thus forming a solvate. If the solvent is waterthe solvate formed is a hydrate and if the solvent is alcohol, thesolvate formed is an alcoholate. Hydrates are formed by the combinationof one or more molecules of water with one molecule of the substance inwhich the water retains its molecular state as H₂O.

The synthesized compounds can be separated from a reaction mixture andfurther purified by a method such as column chromatography, highpressure liquid chromatography, or recrystallization. As can beappreciated by the skilled artisan, further methods of synthesizing thecompounds of the formulae herein will be evident to those of ordinaryskill in the art. Additionally, the various synthetic steps may beperformed in an alternate sequence or order to give the desiredcompounds. In addition, the solvents, temperatures, reaction durations,etc. delineated herein are for purposes of illustration only and one ofordinary skill in the art will recognize that variation of the reactionconditions can produce the desired bridged macrocyclic products of thepresent application. Synthetic chemistry transformations and protectinggroup methodologies (protection and deprotection) useful in synthesizingthe compounds described herein are known in the art and include, forexample, those such as described in R. Larock, Comprehensive OrganicTransformations, VCH Publishers (1989); T. W. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons(1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents forOrganic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed.,Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons(1995), and subsequent editions thereof.

The compounds of this application may be modified by appending variousfunctionalities via any synthetic means delineated herein to enhanceselective biological properties. Such modifications are known in the artand include those which increase biological penetration into a givenbiological system (e.g., blood, lymphatic system, central nervoussystem), increase oral availability, increase solubility to allowadministration by injection, alter metabolism and alter rate ofexcretion.

The compounds of the application are defined herein by their chemicalstructures and/or chemical names. Where a compound is referred to byboth a chemical structure and a chemical name, and the chemicalstructure and chemical name conflict, the chemical structure isdeterminative of the compound's identity.

The recitation of a listing of chemical groups in any definition of avariable herein includes definitions of that variable as any singlegroup or combination of listed groups. The recitation of an embodimentfor a variable herein includes that embodiment as any single embodimentor in combination with any other embodiments or portions thereof.

Methods of Synthesizing the Compounds

A compound of the present application may be made by a variety ofmethods, including standard chemistry. The synthetic processes of theapplication can tolerate a wide variety of functional groups, thereforevarious substituted starting materials can be used. The processesgenerally provide the desired final compound at or near the end of theoverall process, although it may be desirable in certain instances tofurther convert the compound to a pharmaceutically acceptable salt,ester, or prodrug thereof. Suitable synthetic routes are depicted in theschemes below.

A compound of the present application can be prepared in a variety ofways using commercially available starting materials, compounds known inthe literature, or from readily prepared intermediates, by employingstandard synthetic methods and procedures either known to those skilledin the art, or which will be apparent to the skilled artisan in light ofthe teachings herein. Standard synthetic methods and procedures for thepreparation of organic molecules and functional group transformationsand manipulations can be obtained from the relevant scientificliterature or from standard textbooks in the field. Although not limitedto any one or several sources, classic texts such as Smith, M. B.,March, J., March's Advanced Organic Chemistry: Reactions, Mechanisms,and Structure, 5^(th) edition, John Wiley & Sons: New York, 2001; andGreene, T. W., Wuts, P. G. M., Protective Groups in Organic Synthesis,3^(rd) edition, John Wiley & Sons: New York, 1999, incorporated byreference herein, are useful and recognized reference textbooks oforganic synthesis known to those in the art. The following descriptionsof synthetic methods are designed to illustrate, but not to limit,general procedures for the preparation of a compound of the presentapplication.

A compound disclosed herein may be prepared by methods known in the artof organic synthesis as set forth in part by the following syntheticschemes. In the schemes described below, it is well understood thatprotecting groups for sensitive or reactive groups are employed wherenecessary in accordance with general principles or chemistry. Protectinggroups are manipulated according to standard methods of organicsynthesis (T. W. Greene and P. G. M. Wuts, “Protective Groups in OrganicSynthesis”, Third edition, Wiley, New York 1999). These groups areremoved at a convenient stage of the compound synthesis using methodsthat are readily apparent to those skilled in the art. The selectionprocesses, as well as the reaction conditions and order of theirexecution, shall be consistent with the preparation of a compounddisclosed herein.

Those skilled in the art will recognize if a stereocenter exists in acompound disclosed herein. Accordingly, the present application includesboth possible stereoisomers (unless specified in the synthesis) andincludes not only racemic compounds but the individual enantiomersand/or diastereomers as well. When a compound is desired as a singleenantiomer or diastereomer, it may be obtained by stereospecificsynthesis or by resolution of the final product or any convenientintermediate. Resolution of the final product, an intermediate, or astarting material may be affected by any suitable method known in theart. See, for example, “Stereochemistry of Organic Compounds” by E. L.Eliel, S. H. Wilen, and L. N. Mander (Wiley-Interscience, 1994).

All the abbreviations used in this application are found in “ProtectiveGroups in Organic Synthesis” by John Wiley & Sons, Inc, or the MERCKINDEX by MERCK & Co., Inc, or other chemistry books or chemicalscatalogs by chemicals vendor such as Aldrich, or according to usage knowin the art.

By way of example, a compound of the present application can besynthesized using the methods described below, together with syntheticmethods known in the art of synthetic organic chemistry, or variationsthereon as appreciated by those skilled in the art. Preferred methodsinclude but are not limited to those methods described below.

In one embodiment, a compound of the present application can besynthesized by following the steps outlined in General Scheme A.Starting materials are either commercially available or made by knownprocedures in the reported literature or as illustrated.

In one embodiment, a compound of the present application may also beprepared according to General Scheme B. Starting materials are eithercommercially available or made by known procedures in the reportedliterature or as illustrated.

In one embodiment, a compound of the present application may also beprepared according to General Scheme C. Starting materials are eithercommercially available or made by known procedures in the reportedliterature or as illustrated.

In one embodiment, a compound of the present application may also beprepared according to General Scheme D. Starting materials are eithercommercially available or made by known procedures in the reportedliterature or as illustrated.

In one embodiment, a compound of the present application may also beprepared according to General Scheme E. Starting materials are eithercommercially available or made by known procedures in the reportedliterature or as illustrated.

A mixture of enantiomers, diastereomers, and/or cis/trans isomersresulting from the processes described above can be separated into theirsingle components by chiral salt technique, chromatography using normalphase, or reverse phase or chiral column, depending on the nature of theseparation.

It should be understood that in the description and formulae shownabove, the various groups, such as R₁-R₆, m, and n, are as definedherein, except where otherwise indicated. Furthermore, for syntheticpurposes, the compounds in the Schemes are mere representatives withelected substituents to illustrate the general synthetic methodology ofa compound disclosed herein.

Starting materials, reagents and solvents were purchased from commercialsuppliers and were used without further purification unless otherwisenoted. All reactions were monitored using a Waters Acquity UPLC/MSsystem (Waters PDA eλ, Detector, QDa Detector, Sample manager-FL, BinarySolvent Manager) using Acquity UPLC® BEH C18 column (2.1×50 mm, 1.7 μmparticle size): solvent gradient=85% A at 0 min, 1% A at 1.6 min;solvent A=0.1% formic acid in Water; solvent B=0.1% formic acid inAcetonitrile; flow rate: 0.6 mL/min. Reaction products were purified byflash column chromatography using CombiFlash®Rf with Teledyne IscoRediSep®R_(f) columns (4 g, 12 g, 24 g, 40 g, or 80 g) and Waters HPLCsystem using SunFire™ Prep C18 column (19×100 mm, 5 μm particle size):solvent gradient=80% A at 0 min, 10% A at 25 min; solvent A=0.035% TFAin Water; solvent B=0.035% TFA in MeOH; flow rate: 25 mL/min. ¹H NMRspectra were recorded on 500 MHz Bruker Advance III spectrometers.Chemical shifts are reported relative to methanol (δ=3.30), chloroform(δ=7.24) or dimethyl sulfoxide (δ=2.50) for ¹H NMR and ¹³C NMR. Data arereported as (br=broad, s=singlet, d=doublet, t=triplet, q=quartet,m=multiplet).

Biological Assays

A compound of the present application can be tested for its activitywith various biological assays. Suitable assays include, but are notlimited to, western blot analysis, MTS assay, and cell titer gloluminescent cell viability assay. Non-limiting, representative assaysare described briefly below.

Proliferation Inhibition Assay

Cell growth inhibition can be assessed by MTS assay or by Cell Titer GloLuminescent Cell viability assay (Promega®). Cells are seeded and growin culture plates before they are exposed to representative compounds ofthe application for various duration. The viability of the cells arethen assessed. Data are normalized to untreated cells and displayedgraphically using GraphPad Prism (GraphPad Software, Inc.). The growthcurves can be fitted using a nonlinear regression model with sigmoidaldose response.

Western Blot Analysis

Cells are seeded and grow in culture plates, and then treated withrepresentative compounds of the application the following day forvarious duration. Cells are washed with PBS and lysed. The lysates areseparated by SDS-PAGE gel, transferred to nitrocellulose membranes, andprobed with the appropriate antibodies, such as phospho-EGFR(Tyr1068)(3777), total EGFR (2232), p-Akt(Ser473) (4060), total Akt (9272),p-ERK(Thr202/Tyr204) (4370), total ERK (9102), and HSP90 (SC-7947).

In addition, various types of cell lines may be used in testing thecompound of the present application. Non-limiting illustrative celllines are listed in Table 7 below.

TABLE 7  Target Cell Line Name Amino Acid Change Nucleotide Change EGFRIns GY D770delinsGY 2308_2309InsGTT Ins SVD D770_N771insSVD2301_2309DupCAGCGTGGA Ins ASV V769_D770insASV 2297_2305DupTGGCCAGCGIns HH Y764_V765insHH 2290_2291InsACCATC Ins H H773dupH 2316_2317InsCACIns NPG D770_N771insNPG 2309_2310insCAACCCCGG DFCI 58 (orH773_V774insNPH 2311_2319dupAACCCCCAC DFCI 58-229) DFCI 127 (orP772_H773insPNP 2317_2318insCGAACCCCC DFCI 127c) DFCI 362JCN771_P772insH HER2 Ins YVMA A775_G776insYVMA 2311_2322dup Ins VCG776delinsVC 2326_2327insIGT Ins GSP P780_Y781insGSP2331_2339dupGGGCTCCCC Ins WLV M774delinsWLV 2320delinsTGGCTGG Ins CPGG778_S779insCPG 2335_2336insGCCCAGGCTMethods of the Application

Another aspect of the present application relates to a method ofmodulating (e.g., inhibiting or decreasing) EGFR and/or HER2, and/or amutant thereof, comprising administering to a subject in need thereof aneffective amount of a compound of the present application (e.g., acompound of Formula I), or a pharmaceutically acceptable salt or esterthereof.

Another aspect of the present application relates to a method oftreating or preventing a disease or disorder (e.g., cancer) in whichEGFR and/or HER2, and/or a mutant thereof, plays a role, comprisingadministering to a subject in need thereof an effective amount of acompound of the present application (e.g., a compound of Formula I), ora pharmaceutically acceptable salt or ester thereof.

In some embodiments, the disease or disorder is resistant to an EGFRtargeted therapy and/or a HER2 targeted therapy. In some embodiments,the EGFR targeted therapy and/or the HER2 targeted therapy is a therapywith an inhibitor of EGFR, HER2, and/or a mutant thereof, such as theinhibitors described herein.

In some embodiments, the disease is cancer or a proliferative disease.

In some embodiments, the cancer cell comprises a mutant EGFR and/or amutant HER2. In some embodiments, the cancer is a cancer of B cellorigin. In some embodiments, the cancer is a lineage dependent cancer.In some embodiments, the cancer is a lineage dependent cancer where EGFRand/or HER2, and/or a mutant thereof, plays a role in the initiationand/or development of the cancer.

In some embodiments, the subject is identified as being in need ofmodulation (e.g., inhibition or decrease) of EGFR or a mutant thereofand/or HER2 or a mutant thereof for the treatment or prevention of thedisease or disorder.

In some embodiments, the application provides a method of treating anyof the disorders described herein, wherein the subject is a human. Insome embodiments, the application provides a method of preventing any ofthe disorders described herein, wherein the subject is a human.

Another aspect of the present application relates to a compound of thepresent application (e.g., a compound of Formula I), or apharmaceutically acceptable salt or ester thereof, for modulating (e.g.,inhibiting or decreasing) EGFR or a mutant thereof and/or HER2 or amutant thereof; for treating or preventing a disease or disorder, suchas a kinase mediated disease or disorder; for treating or preventing adisease or disorder resistant to an EGFR targeted therapy and/or a HER2targeted therapy; for treating or preventing cancer, wherein the cancercell comprises a mutant EGFR and/or a mutant HER2; or for treating orpreventing a disease or disorder, such as a kinase mediated disease ordisorder in a subject identified as being in need of modulation (e.g.,inhibition or decrease) of EGFR or a mutant thereof and/or HER2 or amutant thereof for the treatment or prevention of the disease ordisorder.

Another aspect of the present application relates to a compound of thepresent application (e.g., a compound of Formula I), or apharmaceutically acceptable salt or ester thereof, for use in themodulation (e.g., inhibition or decrease) of EGFR or a mutant thereofand/or HER2 or a mutant thereof; in the treatment or prevention of adisease or disorder, such as a kinase mediated disease or disorder; inthe treatment or prevention of a disease or disorder resistant to anEGFR targeted therapy and/or a HER2 targeted therapy; in the treatmentor prevention of cancer, wherein the cancer cell comprises a mutant EGFRand/or a mutant HER2; or in the treatment or prevention of a disease ordisorder, such as a kinase mediated disease or disorder in a subjectidentified as being in need of modulation (e.g., inhibition or decrease)of EGFR or a mutant thereof and/or HER2 or a mutant thereof for thetreatment or prevention of the disease or disorder.

Another aspect of the present application relates to use of a compoundof the present application (e.g., a compound of Formula I), or apharmaceutically acceptable salt or ester thereof, in the modulation(e.g., inhibition or decrease) of EGFR or a mutant thereof and/or HER2or a mutant thereof; in the treatment or prevention of a disease ordisorder, such as a kinase mediated disease or disorder; in thetreatment or prevention of a disease or disorder resistant to an EGFRtargeted therapy and/or a HER2 targeted therapy; in the treatment orprevention of cancer, wherein the cancer cell comprises a mutant EGFRand/or a mutant HER2; or in the treatment or prevention of a disease ordisorder, such as a kinase mediated disease or disorder in a subjectidentified as being in need of modulation (e.g., inhibition or decrease)of EGFR or a mutant thereof and/or HER2 or a mutant thereof for thetreatment or prevention of the disease or disorder.

Another aspect of the present application relates to a compound of thepresent application (e.g., a compound of Formula I), or apharmaceutically acceptable salt or ester thereof, for use in themanufacture of a medicament for the modulation (e.g., inhibition ordecrease) of EGFR or a mutant thereof and/or HER2 or a mutant thereof;for the treatment or prevention of a disease or disorder, such as akinase mediated disease or disorder; for the treatment or prevention ofa disease or disorder resistant to an EGFR targeted therapy and/or aHER2 targeted therapy; for the treatment or prevention of cancer,wherein the cancer cell comprises a mutant EGFR and/or a mutant HER2; orfor the treatment or prevention of a disease or disorder, such as akinase mediated disease or disorder in a subject identified as being inneed of modulation (e.g., inhibition or decrease) of EGFR or a mutantthereof and/or HER2 or a mutant thereof for the treatment or preventionof the disease or disorder.

Another aspect of the present application relates to use of a compoundof the present application (e.g., a compound of Formula I), or apharmaceutically acceptable salt or ester thereof, in the manufacture ofa medicament for the modulation (e.g., inhibition or decrease) of EGFRor a mutant thereof and/or HER2 or a mutant thereof; for the treatmentor prevention of a disease or disorder, such as a kinase mediateddisease or disorder; for the treatment or prevention of a disease ordisorder resistant to an EGFR targeted therapy and/or a HER2 targetedtherapy; for the treatment or prevention of cancer, wherein the cancercell comprises a mutant EGFR and/or a mutant HER2; or for the treatmentor prevention of a disease or disorder, such as a kinase mediateddisease or disorder in a subject identified as being in need ofmodulation (e.g., inhibition or decrease) of EGFR or a mutant thereofand/or HER2 or a mutant thereof for the treatment or prevention of thedisease or disorder.

In some embodiments, the EGFR is a wild-type EFGR. In other embodiments,the EFGR has one or more mutations, such as those described herein. Insome embodiments, the HER2 is a wild-type HER2. In other embodiments,the HER2 has one or more mutations, such as those described herein.

One aspect of this application provides compounds that are useful forthe treatment of diseases, disorders, and conditions characterized byexcessive or abnormal cell proliferation. Such diseases include, but arenot limited to, a proliferative or hyperproliferative disease. Examplesof proliferative and hyperproliferative diseases include, withoutlimitation, cancer. The term “cancer” includes, but is not limited to,the following cancers: breast, ovary; cervix; prostate; testis,genitourinary tract; esophagus; larynx, glioblastoma; neuroblastoma;stomach; skin, keratoacanthoma; lung, epidermoid carcinoma, large cellcarcinoma, small cell carcinoma, lung adenocarcinoma, bone; colon;colorectal; adenoma; pancreas, adenocarcinoma; thyroid, follicularcarcinoma, undifferentiated carcinoma, papillary carcinoma; seminoma;melanoma; sarcoma; bladder carcinoma; liver carcinoma and biliarypassages; kidney carcinoma; myeloid disorders; lymphoid disorders,Hodgkin's, hairy cells; buccal cavity and pharynx (oral), lip, tongue,mouth, pharynx; small intestine; colonrectum, large intestine, rectum,brain and central nervous system; chronic myeloid leukemia (CML), andleukemia. The term “cancer” includes, but is not limited to, thefollowing cancers: myeloma, lymphoma, or a cancer selected from gastric,renal, or and the following cancers: head and neck, oropharangeal,non-small cell lung cancer (NSCLC), endometrial, hepatocarcinoma,Non-Hodgkins lymphoma, and pulmonary.

The term “cancer” refers to any cancer caused by the proliferation ofmalignant neoplastic cells, such as tumors, neoplasms, carcinomas,sarcomas, leukemias, lymphomas and the like. For example, cancersinclude, but are not limited to, mesothelioma, leukemias and lymphomassuch as cutaneous T-cell lymphomas (CTCL), noncutaneous peripheralT-cell lymphomas, lymphomas associated with human T-cell lymphotrophicvirus (HTLV) such as adult T-cell leukemia/lymphoma (ATLL), B-celllymphoma, acute nonlymphocytic leukemias, chronic lymphocytic leukemia,chronic myelogenous leukemia, acute myelogenous leukemia, lymphomas, andmultiple myeloma, non-Hodgkin lymphoma, acute lymphatic leukemia (ALL),chronic lymphatic leukemia (CLL), Hodgkin's lymphoma, Burkitt lymphoma,adult T-cell leukemia lymphoma, acute-myeloid leukemia (AML), chronicmyeloid leukemia (CML), or hepatocellular carcinoma. Further examplesinclude myelodisplastic syndrome, childhood solid tumors such as braintumors, neuroblastoma, retinoblastoma, Wilms' tumor, bone tumors, andsoft-tissue sarcomas, common solid tumors of adults such as head andneck cancers (e.g., oral, laryngeal, nasopharyngeal and esophageal),genitourinary cancers (e.g., prostate, bladder, renal, uterine, ovarian,testicular), lung cancer (e.g., small-cell and non-small cell), breastcancer, pancreatic cancer, melanoma and other skin cancers, stomachcancer, brain tumors, tumors related to Gorlin's syndrome (e.g.,medulloblastoma, meningioma, etc.), and liver cancer. Additionalexemplary forms of cancer which may be treated by the subject compoundsinclude, but are not limited to, cancer of skeletal or smooth muscle,stomach cancer, cancer of the small intestine, rectum carcinoma, cancerof the salivary gland, endometrial cancer, adrenal cancer, anal cancer,rectal cancer, parathyroid cancer, and pituitary cancer.

Additional cancers that the compounds described herein may be useful inpreventing, treating and studying are, for example, colon carcinoma,familiary adenomatous polyposis carcinoma and hereditary non-polyposiscolorectal cancer, or melanoma. Further, cancers include, but are notlimited to, labial carcinoma, larynx carcinoma, hypopharynx carcinoma,tongue carcinoma, salivary gland carcinoma, gastric carcinoma,adenocarcinoma, thyroid cancer (medullary and papillary thyroidcarcinoma), renal carcinoma, kidney parenchyma carcinoma, cervixcarcinoma, uterine corpus carcinoma, endometrium carcinoma, chorioncarcinoma, testis carcinoma, urinary carcinoma, melanoma, brain tumorssuch as glioblastoma, astrocytoma, meningioma, medulloblastoma andperipheral neuroectodermal tumors, gall bladder carcinoma, bronchialcarcinoma, multiple myeloma, basalioma, teratoma, retinoblastoma,choroidea melanoma, seminoma, rhabdomyosarcoma, craniopharyngeoma,osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma,Ewing sarcoma, and plasmocytoma. In one aspect of the application, thepresent application provides for the use of one or more a compound ofthe application in the manufacture of a medicament for the treatment ofcancer, including without limitation the various types of cancerdisclosed herein.

This application further embraces the treatment or prevention of cellproliferative disorders such as hyperplasias, dysplasias andpre-cancerous lesions. Dysplasia is the earliest form of pre-cancerouslesion recognizable in a biopsy by a pathologist. The subject compoundsmay be administered for the purpose of preventing said hyperplasias,dysplasias or pre-cancerous lesions from continuing to expand or frombecoming cancerous. Examples of pre-cancerous lesions may) occur inskin, esophageal tissue, breast and cervical intraepithelial tissue.

Pharmaceutical Compositions

In another aspect, the application provides a pharmaceutical compositioncomprising a compound disclosed herein, or a pharmaceutically acceptableester, salt, or prodrug thereof, together with a pharmaceuticallyacceptable carrier.

A compound of the application can be administered as pharmaceuticalcompositions by any conventional route, in particular enterally, e.g.,orally, e.g., in the form of tablets or capsules, or parenterally, e.g.,in the form of injectable solutions or suspensions, topically, e.g., inthe form of lotions, gels, ointments or creams, or in a nasal orsuppository form. Pharmaceutical compositions comprising a compound ofthe present application in free form or in a pharmaceutically acceptablesalt form in association. For example, oral compositions can be tabletsor gelatin capsules comprising the active ingredient together with a)diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol,cellulose and/or glycine; b) lubricants, e.g., silica, talcum, stearicacid, its magnesium or calcium salt and/or polyethyleneglycol; fortablets also c) binders, e.g., magnesium aluminum silicate, starchpaste, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose and or polyvinylpyrrolidone; if desired d)disintegrants, e.g., starches, agar, alginic acid or its sodium salt, oreffervescent mixtures; and/or e) absorbents, colorants, flavors andsweeteners. Injectable compositions can be aqueous isotonic solutions orsuspensions, and suppositories can be prepared from fatty emulsions orsuspensions. The compositions may be sterilized and/or containadjuvants, such as preserving, stabilizing, wetting or emulsifyingagents, solution promoters, salts for regulating the osmotic pressureand/or buffers. In addition, they may also contain other therapeuticallyvaluable substances. Suitable formulations for transdermal applicationsinclude an effective amount of a compound of the present applicationwith a carrier. A carrier can include absorbable pharmacologicallyacceptable solvents to assist passage through the skin of the host. Forexample, transdermal devices are in the form of a bandage comprising abacking member, a reservoir containing the compound optionally withcarriers, optionally a rate controlling barrier to deliver the compoundto the skin of the host at a controlled and predetermined rate over aprolonged period of time, and means to secure the device to the skin.Matrix transdermal formulations may also be used. Suitable formulationsfor topical application, e.g., to the skin and eyes, are preferablyaqueous solutions, ointments, creams or gels well-known in the art. Suchmay contain solubilizers, stabilizers, tonicity enhancing agents,buffers and preservatives.

The pharmaceutical compositions of the present application comprise atherapeutically effective amount of a compound of the presentapplication formulated together with one or more pharmaceuticallyacceptable carriers. As used herein, the term “pharmaceuticallyacceptable carrier” means a non-toxic, inert solid, semi-solid or liquidfiller, diluent, encapsulating material or formulation auxiliary of anytype. The pharmaceutical compositions of this application can beadministered to humans and other animals orally, rectally, parenterally,intracistemally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), buccally, or as an oral or nasal spray.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups andelixirs. In addition to the active compounds, the liquid dosage formsmay contain inert diluents commonly used in the art such as, forexample, water or other solvents, solubilizing agents and emulsifierssuch as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils (in particular, cottonseed, groundnut,corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof. Besides inert diluents, the oralcompositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

In order to prolong the effect of a drug, it is often desirable to slowthe absorption of the drug from subcutaneous or intramuscular injection.This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material with poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolutionwhich, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing a compound of thisapplication with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid compositions of a similar type may also be employed as fillers insoft and hard filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like.

The active compounds can also be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents.

Dosage forms for topical or transdermal administration of a compound ofthis application include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, eye ointments, powders and solutionsare also contemplated as being within the scope of this application.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this application, excipients such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to a compound of thisapplication, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants suchas chlorofluorohydrocarbons.

Transdermal patches have the added advantage of providing controlleddelivery of a compound to the body. Such dosage forms can be made bydissolving or dispensing the compound in the proper medium. Absorptionenhancers can also be used to increase the flux of the compound acrossthe skin. The rate can be controlled by either providing a ratecontrolling membrane or by dispersing the compound in a polymer matrixor gel.

According to the methods of treatment of the present application,disorders are treated or prevented in a subject, such as a human orother animal, by administering to the subject a therapeuticallyeffective amount of a compound of the application, in such amounts andfor such time as is necessary to achieve the desired result. The term“therapeutically effective amount” of a compound of the application, asused herein, means a sufficient amount of the compound so as to decreasethe symptoms of a disorder in a subject. As is well understood in themedical arts a therapeutically effective amount of a compound of thisapplication will be at a reasonable benefit/risk ratio applicable to anymedical treatment.

In general, a compound of the application will be administered intherapeutically effective amounts via any of the usual and acceptablemodes known in the art, either singly or in combination with one or moretherapeutic agents. A therapeutically effective amount may vary widelydepending on the severity of the disease, the age and relative health ofthe subject, the potency of the compound used and other factors.Therapeutic amounts or doses will also vary depending on route ofadministration, as well as the possibility of co-usage with otheragents.

Upon improvement of a subject's condition, a maintenance dose of acompound, composition or combination of this application may beadministered, if necessary. Subsequently, the dosage or frequency ofadministration, or both, may be reduced, as a function of the symptoms,to a level at which the improved condition is retained when the symptomshave been alleviated to the desired level, treatment should cease. Thesubject may, however, require intermittent treatment on a long-termbasis upon any recurrence of disease symptoms.

It will be understood, however, that the total daily usage of thecompounds and compositions of the present application will be decided bythe attending physician within the scope of sound medical judgment. Thespecific inhibitory dose for any particular patient will depend upon avariety of factors including the disorder being treated and the severityof the disorder; the activity of the specific compound employed; thespecific composition employed; the age, body weight, general health, sexand diet of the patient; the time of administration, route ofadministration, and rate of excretion of the specific compound employed;the duration of the treatment; drugs used in combination or coincidentalwith the specific compound employed; and like factors well known in themedical arts.

The term “pharmaceutical combination” as used herein means a productthat results from the mixing or combining of more than one activeingredient and includes both fixed and non-fixed combinations of theactive ingredients. The term “fixed combination” means that the activeingredients, e.g., a compound of the application and a co-agent, areboth administered to a patient simultaneously in the form of a singleentity or dosage. The term “non-fixed combination” means that the activeingredients, e.g., a compound of the application and a co-agent, areboth administered to a patient as separate entities eithersimultaneously, concurrently or sequentially with no specific timelimits, wherein such administration provides therapeutically effectivelevels of the two compounds in the body of the patient. The latter alsoapplies to cocktail therapy, e.g., the administration of three or moreactive ingredients.

Some examples of materials which can serve as pharmaceuticallyacceptable carriers include, but are not limited to, ion exchangers,alumina, aluminum stearate, lecithin, serum proteins, such as humanserum albumin, buffer substances such as phosphates, glycine, sorbicacid, or potassium sorbate, partial glyceride mixtures of saturatedvegetable fatty acids, water, salts or electrolytes, such as protaminesulfate, disodium hydrogen phosphate, potassium hydrogen phosphate,sodium chloride, zinc salts, colloidal silica, magnesium trisilicate,polyvinyl pyrrolidone, polyacrylates, waxes,polyethylenepolyoxypropylene-block polymers, wool fat, sugars such aslactose, glucose and sucrose; starches such as corn starch and potatostarch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethyl cellulose and cellulose acetate; powdered tragacanth;malt; gelatin; talc; excipients such as cocoa butter and suppositorywaxes, oils such as peanut oil, cottonseed oil; safflower oil; sesameoil; olive oil; corn oil and soybean oil; glycols; such a propyleneglycol or polyethylene glycol; esters such as ethyl oleate and ethyllaurate, agar; buffering agents such as magnesium hydroxide and aluminumhydroxide; alginic acid; pyrogen-free water, isotonic saline; Ringer'ssolution; ethyl alcohol, and phosphate buffer solutions, as well asother non-toxic compatible lubricants such as sodium lauryl sulfate andmagnesium stearate, as well as coloring agents, releasing agents,coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the composition,according to the judgment of the formulator. The protein kinaseinhibitors or pharmaceutical salts thereof may be formulated intopharmaceutical compositions for administration to animals or humans.These pharmaceutical compositions, which comprise an amount of theprotein inhibitor effective to treat or prevent a proteinkinase-mediated condition and a pharmaceutically acceptable carrier, areother embodiments of the present application.

In another aspect, the application provides a kit comprising a compoundcapable of inhibiting kinase activity selected from one or morecompounds of disclosed herein, or a pharmaceutically acceptable salt,hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, andinstructions for use in treating cancer.

In another aspect, the application provides a kit comprising a compoundcapable of inhibiting EGFR and/or HER2 activity selected from a compounddisclosed herein, or a pharmaceutically acceptable salt, hydrate,solvate, prodrug, stereoisomer, or tautomer thereof.

The application is further illustrated by the following examples andsynthesis schemes, which are not to be construed as limiting thisapplication in scope or spirit to the specific procedures hereindescribed. It is to be understood that the examples are provided toillustrate certain embodiments and that no limitation to the scope ofthe application is intended thereby. It is to be further understood thatresort may be had to various other embodiments, modifications, andequivalents thereof which may suggest themselves to those skilled in theart without departing from the spirit of the present application and/orscope of the appended claims.

EXAMPLES Example 1. Synthesis of Compound 1 Step 1: Synthesis of ethyl4-((3-((tert-butoxycarbonyl)amino)phenyl)amino)-2-(methylthio)pyrimidine-5-carboxylate

To a solution of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate(9.30 g, 40.0 mmol) and tert-butyl (3-aminophenyl)carbamate (10.0 g,48.0 mmol) in N,N-dimethylformamide (100 mL) was added potassiumcarbonate (11.0 g, 80.0 mmol). After stirring for 2 hr at 80° C., thereaction mixture was cooled to room temperature and the cold water wasadded to the mixture. The precipitate was filtered and dried by blowingnitrogen gas to obtain ethyl4-((3-((tert-butoxycarbonyl)amino)phenyl)amino)-2-(methylthio)pyrimidine-5-carboxylate(15.4 g, 95%) as a yellow solid.

Step 2: Synthesis of tert-Butyl(3-((5-(hydroxymethyl)-2-(methylthio)pyrimidin-4-yl)amino)phenyl)carbamate

To a solution of ethyl4-((3-((tert-butoxycarbonyl)amino)phenyl)amino)-2-(methylthio)pyrimidine-5-carboxylate(7.0 g, 17.31 mmol) in dry THF (60 mL) was added dropwise 2 M lithiumaluminum hydride solution in THF (21.6 mL, 43.3 mmol) at −78° C. Thereaction mixture was slowly warmed up to −20° C. and stirred for 4 hr.The reaction mixture was quenched by adding Rochelle's solution andstirred for 1 hr. The white precipitate was filtered and the filtratewas concentrated under reduced pressure. The residue was re-dissolved inEtOAc, washed with sat. NaHCO₃, water and brine. The organic layer wasdried over Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by flash column chromatography (EtOAc:Hexane=2:8 to8:2) to give tert-butyl(3-((5-(hydroxymethyl)-2-(methylthio)pyrimidin-4-yl)amino)phenyl)carbamate(4.10 g, 65%) a sticky oil.

Step 3: Synthesis oftert-Butyl(3-((5-formyl-2-(methylthio)pyrimidin-4-yl)amino)phenyl)carbamate

To a solution tert-butyl(3-((5-(hydroxymethyl)-2-(methylthio)pyrimidin-4-yl)amino)phenyl)carbamate(980 mg, 2.70 mmol) in dry DCM (20 mL) was added activated MnO₂ (1.20 g,13.5 mmol). After stirring for 4 hr at 35° C., the suspension wasfiltered through pad of celite. The filtrate was washed with water,dried over Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by flash column chromatography to give tert-butyl(3-((5-formyl-2-(methylthio)pyrimidin-4-yl)amino)phenyl)carbamate (820mg, 84%) as a yellow solid.

Step 4: Synthesis of tert-butyl(3-(6-(4-fluorophenoxy-2-(methylthio)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)carbamate

The mixture of tert-butyl(3-((5-formyl-2-(methylthio)pyrimidin-4-yl)amino)phenyl)carbamate (260mg, 0.721 mmol), ethyl 2-(4-fluorophenoxy)acetate (214 mg, 1.08 mmol),K₂CO₃ (300 mg, 2.16 mmol) were dissolved in dry N-methyl-2pyrrolidone (5mL). After stirring for 6 hr at 120° C., the reaction mixture was cooledto room temperature and poured into excess water. The resultingprecipitate was filtered, washed with water. The sold was dried byblowing nitrogen gas to obtain tert-butyl(3-(6-(4-fluorophenoxy)-2-(methylthio)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)carbamate(285 mg, 80%) as a brown solid.

Step 5: Synthesis of tert-butyl(3-(6-(4-fluorophenoxy)-2-(methylsulfonyl)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)carbamate

To a solution of tert-butyl(3-(6-(4-fluorophenoxy)-2-(methylthio)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)carbamate(200 mg, 0.404 mmol) in dry DCM (4 mL) was added 3-chloroperbenzoic acid(300 mg, 1.46 mmol) at 0° C. The mixture was stirred at 0° C. for 15 minand then, stirred at room temperature for 1 hr. After that, the reactionmixture was diluted with DCM and quenched using sat. sodium thiosulfate.The organic layer was washed with sat. NaHCO₃ and bring, dried overNa₂SO₄, filtered and concentrated. The crude compound was used to nextstep without further purification.

Step 6: Synthesis of8-(3-aminophenyl)-6-(4-fluorophenoxy)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one

To a solution of tert-butyl(3-(6-(4-fluorophenoxy)-2-(methylsulfonyl)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)carbamatein 2-butanol (4 mL) were added 1-methyl-1H-pyrazol-4-amine hydrochloride(79.5 mg, 0.600 mmol) and trifluoroacetic acid (1.5 mL). The resultingmixture was stirred at 80° C. for 8 hr and then, cooled to roomtemperature. The reaction mixture was diluted with EtOAc, washed withsat. NaHCO₃ and brine. The organic layer was dried over Na₂SO₄, filteredand concentrated under reduced pressure. The crude product was used tonext step without further purification.

Step 7: Synthesis ofN-(3-(6-(4-fluorophenoxy)-2-((1-methyl-1H-pyrazol-4-yl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide

To a solution of8-(3-aminophenyl)-6-(4-fluorophenoxy)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-onein THF/sat.NaHCO₃ mixture (1:1, 2 mL) was added dropwise acryloylchloride (32.0 μL, 0.400 mmol). After stirring for 30 min, the reactionmixture was diluted with DCM and washed with water and brine. Theorganic layer was dried over Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by prep HPLC to giveN-(3-(6-(4-fluorophenoxy)-2-((1-methyl-1H-pyrazol-4-yl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide(Compound 1; 48.0 mg, 48%, three steps) as a yellow solid.

¹H NMR (500 MHz, DMSO-d6) δ 10.43 (s, 1H), 9.97 (s, 1H), 8.71 (s, 1H),7.87 (d, J=8.2 Hz, 1H), 7.76 (s, 1H), 7.65-7.58 (m, 2H), 7.25-7.10 (m,6H), 6.79 (s, 1H), 6.44 (dd, J=16.9, 10.2 Hz, 1H), 6.26 (dd, J=16.9, 2.0Hz, 1H), 5.77 (dd, J=10.7, 1.8 Hz, 1H), 3.52 (s, 3H); LC/MS (ESI) m/z498.50 [M+H]⁺.

Example 2. Synthesis of Compound 2

Compound 2 was synthesized according to the procedures described inExample 1.

¹H NMR (500 MHz; DMSO-d6) δ 10.43 (s, 1H), 9.98 (s, 1H), 8.71 (s, 1H),7.87 (d, J=8.2 Hz, 1H), 7.77 (s, 1H), 7.65-7.58 (m, 2H), 7.47 (ddd,J=11.3, 8.7, 2.9, 1H), 7.36 (td, J=9.3, 5.5, 1H), 7.17-7.06 (m, 3H),6.79 (s, 1H), 6.44 (dd, J=17.1, 10.1 Hz, 1H), 6.26 (dd, J=17.1, 1.8 Hz,1H), 5.77 (dd, J=10.7, 1.8 Hz, 1H), 3.52 (s, 3H); LC/MS (ESI) m/z 516.52[M+H]⁺.

Example 3. Synthesis of Compound 3

Compound 3 was synthesized according to the procedures described inExample 1.

¹H NMR (500 MHz, DMSO-d6) δ 10.43 (s, 1H), 9.99 (s, 1H), 8.72 (s, 1H),7.92 (d, J=8.2 Hz, 1H), 7.72 (s, 1H), 7.66-7.57 (m, 2H), 7.51-7.43 (m,1H), 7.35 (td, J=9.3, 5.5, 1H), 7.19 (s, 1H), 7.15-7.05 (m, 2H), 6.90(s, 1H), 6.44 (dd, J=17.1, 10.1 Hz, 1H), 6.26 (dd, J=17.1, 1.9 Hz, 1H),5.77 (dd, J=10.7, 1.8 Hz, 1H), 3.64-3.55 (m, 1H), 2.98-2.77 (m, 2H),2.26 (br s, 3H), 2.17-1.99 (m, 2H), 1.83-1.71 (m, 2H), 1.68-1.55 (m,2H); LC/MS (ESI) m/z 599.65 [M+H]⁺.

Example 4. Synthesis of Compound 4

Compound 4 was synthesized according to the procedures described inExample 1.

¹H NMR (500 MHz; DMSO-d6) δ 10.42 (s, 1H), 9.20 (s, 1H), 8.70 (s, 1H),7.86 (d, J=7.6 Hz, 1H), 7.72 (br s, 1H), 7.64-7.58 (m, 2H), 7.50-7.43(m, 1H), 7.36 (td, J=9.2, 5.5 Hz, 1H), 7.17-7.04 (m, 2H), 6.59 (s, 1H),6.44 (dd, J=16.8, 10.1 Hz, 1H), 6.26 (dd, J=16.9, 1.8 Hz, 1H), 5.80-5.75(m, 1H), 3.75 (s, 3H), 3.36 (s, 3H); LC/MS (ESI) m/z 546.53 [M+H]⁺.

Example 5. Synthesis of Compound 5

Compound 5 was synthesized according to the procedures described inExample 1.

¹H NMR (500 MHz, DMSO-d6) δ 10.37 (s, 1H), 10.21 (s, 1H), 8.78 (s, 1H),7.86 (s, 1H), 7.75 (d, J=8.2 Hz, 1H), 7.61 (s, 1H), 7.59-7.53 (m, 1H),7.53-7.44 (m, 2H), 7.43-7.33 (m, 2H), 7.19 (s, 1H), 7.16-7.06 (m, 2H),6.43 (dd, J=17.1, 10.1 Hz, 1H), 6.23 (br d, J=16.8 Hz, 1H), 5.75 (br d,J=10.4 Hz, 1H); LC/MS (ESI) min 552.53 [M+H]⁺.

Example 6. Synthesis of Compound 6

Compound 6 was synthesized according to the procedures described inExample 1.

¹H NMR (500 MHz, DMSO-d₆) δ 10.39 (s, 1H), 8.71 (s, 1H), 8.10 (s, 1H),7.89 (d, J=7.0 Hz, 1H), 7.65 (s, 1H), 7.58 (s, 1H), 7.55-7.43 (m, 2H),7.37 (td, J=9.2, 5.6 Hz, 1H), 7.29 (d, J=8.9 Hz, 1H), 7.13-7.06 (m, 2H),6.57-6.52 (m, 1H), 6.44 (dd, J=17.1, 10.1 Hz, 1H), 6.23 (dd, J=16.8, 1.6Hz, 1H), 6.04 (br s, 1H), 5.77 (dd, J=10.1, 1.8 Hz, 1H), 3.77 (s, 3H),3.10 (br s, 4H), 2.68 (br s, 4H), 2.41 (br s, 3H); LC/MS (ESI) m/z640.71 [M+H]⁺.

Example 7. Synthesis of Compound 7

Compound 7 was synthesized according to the procedures described inExample 1.

¹H NMR (500 MHz, DMSO-d₆) δ 10.47 (s, 1H), 10.03-9.68 (m, 1H), 8.73 (s,1H), 7.97 (br s, 1H), 7.64 (s, 1H), 7.60 (s, 1H), 7.55 (t, J=7.9 Hz,1H), 7.51-7.44 (m, 1H), 7.36 (td, J=9.3, 5.5 Hz, 1H), 7.28-7.14 (m, 2H),7.12-7.04 (m, 2H), 6.59 (br s, 2H) 6.47 (dd, J=17.1, 10.1 Hz, 1H), 6.27(dd, J=17.1, 1.5 Hz, 1H), 6.04 (br s, 1H), 5.77 (dd, J=10.1, 1.8 Hz,1H), 3.55 (br s, 4H), 3.13-2.88 (m, 4H), 2.76 (br s, 3H), 2.67-2.47 (m,5H), 1.82 (br s, 2H), 1.51 (br s, 2H); LC/MS (ESI) m/z 693.79 [M+H]⁺.

Example 8. Synthesis of Compound 8

Compound 8 was synthesized according to the procedures described inExample 1.

¹NMR (500 MHz, DMSO-d₆) δ 10.42 (br s, 1H), 9.09 (s, 1H), 8.71 (s, 1H),7.86 (d, J=7.6 Hz, 1H), 7.72 (br s, 1H), 7.65-7.55 (m, 2H), 7.47 (ddd,J=11.3, 8.7, 2.7 Hz, 1H), 7.36 (td, J=9.2, 5.5 Hz, 1H), 7.17-7.04 (m,2H), 6.58 (s, 1H), 6.44 (dd, J=16.9, 10.2 Hz, 1H), 6.26 (dd, J=17.1, 1.8Hz, 1H), 5.78 (dd, J=10.1, 1.8 Hz, 1H), 4.08 (q, J=7.0 Hz, 2H), 3.75 (s,3H), 3.35 (s, 3H), 1.26 (t, J=6.9 Hz, 3H); LC/MS (ESI) m/z 560.28[M+H]⁺.

Example 9. Synthesis of Compound 9

Compound 9 was synthesized according to the procedures described inExample 1.

¹NMR (500 MHz, DMSO-d₆) δ 10.44 (s, 1H), 9.99 (s, 1H), 8.72 (s, 1H),7.95 (d, J=7.6 Hz, 1H), 7.69 (s, 1H), 7.65-7.58 (m, 2H), 7.26-7.11 (m,6H), 6.89 (s, 1H), 6.44 (dd, J=10.2, 16.9 Hz, 1H), 6.26 (dd, J=1.8, 17.1Hz, 1H), 5.80-5.73 (m, 1H), 3.68-3.61 (m, 1H), 3.00-2.86 (m, 2H), 2.36(s, 3H), 2.29-2.10 (m, 2H), 1.87-1.76 (m, 2H), 1.74-1.60 (m, 2H); LC/MS(ESI) m/z 581.59 [M+H]⁺.

Example 10. Synthesis of Compound 10

Compound 10 was synthesized according to the procedures described inExample 1.

¹NMR (500 MHz, DMSO-d₆) δ 10.34 (s, 1H), 9.98 (s, 1H), 8.71 (s, 1H),7.84 (d, J=8.2 Hz, 1H), 7.77 (s, 1H), 7.63-7.59 (m, 2H), 7.47 (ddd,J=3.1, 8.7, 11.4 Hz, 1H), 7.36 (td, J=5.5, 9.3 Hz, 1H), 7.14-7.06 (m,3H), 6.78 (s, 1H), 6.73 (dt, J=5.9, 15.4 Hz, 1H), 6.30-6.26 (m, 1H),3.52 (s, 3H), 3.06 (d, J=5.2 Hz, 2H), 2.17 (s, 6H); LCMS (ESI) m/z573.30 [M+H]⁺.

Example 11. Synthesis of Compound 11

Compound 11 was synthesized according to the procedures described inExample 1.

¹NMR (500 MHz, DMSO-d₆) δ 10.45 (s, 1H), 10.28 (s, 1H), 8.83 (s, 1H),8.22 (s, 1H), 7.91 (br t, J=4.0 Hz, 1H), 7.84 (br d, J=8.5 Hz, 1H),7.81-7.79 (m, 1H), 7.71-7.66 (m, 1H), 7.64 (t, J=8.1 Hz, 1H), 7.15 (s,1H), 7.12-7.09 (m, 1H), 6.83 (s, 1H), 6.53 (dd, J=5.4, 10.2 Hz, 1H),6.44 (dd, J=10.2, 17.0 Hz, 1H), 6.26 (dd, J=2.0, 16.9 Hz, 1H), 5.78 (dd,J=1.9, 10.2 Hz, 1H), 3.54 (s, 3H); LC/MS (ESI) m/z 499.40 [M+H].

Example 12. Synthesis of Compound 12

Compound 12 was synthesized according to the procedures described inExample 1.

¹NMR (500 MHz, DMSO-d₆) δ 10.54 (s, 1H), 10.35 (s, 1H), 8.85 (s, 1H),8.22 (s, 1H), 7.91 (br t, J=4.0 Hz, 1H), 7.77 (br d, J=8.2 Hz, 1H),7.73-7.71 (m, 1H), 7.71-7.66 (m, 1H), 7.54 (t, J=8.1 Hz, 1H), 7.19 (brs, 1H), 7.08-7.04 (m, 1H), 6.53 (dd, J=5.5, 10.1 Hz, 1H), 6.43 (dd,J=10.1, 16.8 Hz, 1H), 6.25 (dd, J=1.8, 17.0 Hz, 1H), 5.77 (dd, J=1.9,10.1 Hz, 1H), 5.56 (br, 1H), 3.65 (s, 3H); LC/MS (ESI) m/z 499.40[M+H]⁺.

Example 13. Synthesis of Compound 13

Compound 13 was synthesized according to the procedures described inExample 1.

¹NMR (500 MHz, DMSO-d₆) δ 10.44 (s, 1H), 10.02 (s, 1H), 8.73 (s, 1H),8.13-8.09 (m, 1H), 7.87 (br d, J=8.2 Hz, 1H), 7.85-7.81 (m, 1H), 7.81(s, 1H), 7.77 (br s, 1H), 7.62 (t, J=8.1 Hz, 1H), 7.20 (dd, J=3.4, 8.9Hz, 1H), 7.15 (br d, J=8.2 Hz, 1H), 7.12 (s, 1H), 6.80 (s, 1H), 6.44(dd, J=10.2, 17.0 Hz, 1H), 6.26 (dd, J=1.8, 16.8 Hz, 1H), 5.77 (dd,J=1.8, 10.1 Hz, 1H), 3.52 (s, 3H); LC/MS (ESI) m/z 499.44 [M+H]⁺.

Example 14. Synthesis of Compound 14

Compound was synthesized according to the procedures described inExample 1.

¹NMR (500 MHz, DMSO-d₆) δ 10.34 (s, 1H), 10.24 (br s, 1H), 8.75 (s, 1H),8.12-8.10 (m, 1H), 7.85-7.77 (m, 3H), 7.70-7.67 (m, 1H), 7.52 (t, J=8.1Hz, 1H), 7.20 (dd, J=3.4, 8.9 Hz, 1H), 7.16 (br s, 1H), 7.09 (br d,J=7.9 Hz, 1H), 6.44 (dd, J=10.2, 16.9 Hz, 1H), 6.25 (dd, J=1.9, 17.0 Hz,1H), 5.76 (dd, J=1.9, 10.1 Hz, 1H), 5.58 (br s, 1H), 3.64 (s, 3H); LC/MS(ESI) m/z 499.44 [M+H]⁺.

Example 15. Synthesis of Compound 15 Step 1: Synthesis of6-(2,4-difluorophenoxy)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one

To a solution of 4-amino-2-(methylthio)pyrimidine-5-carbaldehyde (782mg, 4.63 mmol) and ethyl 2-(2,4-difluorophenoxy)acetate (1.30 g, 6.01mmol) in dry N-methyl-2pyrrolidone (12 mL) was added K₂CO₃ (1.78 g, 12.9mmol). After stirring for 8 hr at 100° C., the reaction mixture wascooled to room temperature and poured into excess water. The resultingprecipitate was filtered, washed with water. The sold was dried byblowing nitrogen gas to obtain6-(2,4-difluorophenoxy)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one(1.07 mg, 72%) as a brown solid.

Step 2:(R)-3-(6-(2,4-difluorophenoxy)-2-(methylthio)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)piperidine-1-carboxylate

To a solution of6-(2,4-difluorophenoxy)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one(400 mg, 1.24 mmol), triphenylphosphine (650 mg, 2.48 mmol) andtert-butyl (S)-3-hydroxypiperidine-1-carboxylate (374 mg, 1.86 mmol) wasadded DIAD (0.730 mL, 3.72 mmol) at 0° C. After stirring for 12 hr, themixture was poured into 0.5 N HCl solution. The suspension was filteredand the solid was dried by blowing nitrogen gas to obtain tert-butyl(R)-3-(6-(2,4-difluorophenoxy)-2-(methylthio)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)piperidine-1-carboxylate(407 mg, 65%) as a yellow solid.

Step 3:(R)-3-(6-(2,4-difluorophenoxy)-2-(methylsulfonyl)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)piperidine-1-carboxylate

To a solution of tert-butyl(R)-3-(6-(2,4-difluorophenoxy)-2-(methylthio)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)piperidine-1-carboxylate(300 mg, 0.595 mmol) in dry DCM (6 mL) was added 3-chloroperbenzoic acid(308 mg, 1.78 mmol) at 0° C. The mixture was stirred at 0° C. for 15 minand then, stirred at room temperature for 1 hr. After that, the reactionmixture was diluted with DCM and quenched using sat. sodium thiosulfate.The organic layer was washed with sat. NaHCO₃ and bring, dried overNa₂SO₄, filtered and concentrated. The crude compound was used to nextstep without further purification.

Step 4:(R)-6-(2,4-difluorophenoxy)-2-((1-methyl-1H-pyrazol-4-yl)amino)-8-(piperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one

To a solution of tert-butyl(R)-3-(6-(2,4-difluorophenoxy)-2-(methylsulfonyl)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)piperidine-1-carboxylatein 2-butanol (3.5 mL) were added 1-methyl-1H-pyrazol-4-aminehydrochloride (191 mg, 1.43 mmol) and trifluoroacetic acid (1.5 mL). Theresulting mixture was stirred at 80° C. for 8 hr and then, cooled toroom temperature. The reaction mixture was diluted with EtOAc, washedwith sat. NaHCO₃ and brine. The organic layer was dried over Na₂SO₄,filtered and concentrated under reduced pressure. The crude product wasused to next step without further purification.

Step 5:(R)-8-(1-acryloylpiperidin-3-yl)-6-(2,4-difluorophenoxy)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one

To a solution of(R)-6-(2,4-difluorophenoxy)-2-((1-methyl-1H-pyrazol-4-yl)amino)-8-(piperidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-onein THF/sat.NaHCO₃ mixture (1:1, 4 mL) was added dropwise acryloylchloride (78.0 μL, 0.952 mmol). After stirring for 30 min, the reactionmixture was diluted with DCM and washed with water and brine. Theorganic layer was dried over Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by prep HPLC to give(R)-8-(1-acryloylpiperidin-3-yl)-6-(2,4-difluorophenoxy)-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one(Compound 15; 72.0 mg, 24%, three steps) as a yellow solid.

¹H NMR (500 MHz, DMSO-d₆) δ 9.47 (br s, 1H), 8.65 (s, 1H), 7.76 (s, 1H),7.50 (s, 1H), 7.44 (s, 1H), 7.32 (ddd, J=11.2, 8.6, 3.1 Hz, 1H), 7.21(td, J=9.3, 5.5 Hz, 1H), 7.06-6.97 (m, 1H), 6.74 (dd, J=16.2, 10.7 Hz,1H), 6.09 (dd, J=16.8, 1.8 Hz, 1H), 5.63 (d, J=9.5 Hz, 1H), 5.36 (br s,1H), 4.28 (br s, 2H), 4.01 (br s, 1H), 3.79 (s, 3H), 2.88 (br s, 1H),2.76 (qd, J=12.6, 4.1 Hz, 1H), 1.92 (d, J=13.4 Hz, 1H), 1.82 (d, J=13.1Hz, 1H), 1.61-1.48 (m, 1H); LC/MS (ESI) m/z 508.27 [M+H].

Example 16. Synthesis of Compound 16

Compound 16 was synthesized according to the procedures described inExample 15.

¹H NMR (500 MHz, DMSO-d₆) δ 9.49 (br s, 1H), 8.66 (s, 1H), 7.76 (s, 1H),7.52 (s, 1H), 7.44 (s, 1H), 7.32 (ddd, J=11.4, 8.6, 2.9 Hz, 1H), 7.21(td, J=9.3, 5.5 Hz, 1H), 7.06-6.99 (m, 1H), 6.82 (br d, J=14.0 Hz, 1H),6.68-6.57 (m, 1H), 5.36 (br s, 1H), 4.55-3.92 (br m, 4H), 3.80 (s, 3H),3.65 (br s, 2H), 2.84-2.70 (m, 1H), 2.61 (br s, 6H), 1.93 (d, J=13.4 Hz,1H), 1.82 (d, J=12.2 Hz, 1H), 1.62-1.48 (m, 1H); LC/MS (ESI) m/z 565.33[M+H]⁺.

Example 17. Synthesis of Compound 17

Compound 17 was synthesized according to the procedures described inExample 15.

LC/MS (ESI) m/z 591.36 [M+H]⁺.

Example 18. Synthesis of Compound 18

Compound 18 was synthesized according to the procedures described inExample 15.

¹H NMR (500 MHz, DMSO-d₆) δ 9.47 (br s, 1H), 8.65 (s, 1H), 7.76 (s, 1H),7.50 (s, 1H), 7.44 (s, 1H), 7.32 (ddd, J=11.4, 8.7, 3.1 Hz, 1H), 7.21(td, J=9.2, 5.6 Hz, 1H), 7.06-6.97 (m, 1H), 6.74 (dd, J=15.9, 10.4 Hz,1H), 6.09 (dd, J=16.8, 1.8 Hz, 1H), 5.63 (d, J=9.5 Hz, 1H), 5.37 (br s,1H), 4.29 (br s, 2H), 4.02 (br s, 1H), 3.79 (s, 3H), 2.88 (br s, 1H),2.76 (qd, J=12.4, 4.0 Hz, 1H), 1.92 (d, J=13.4 Hz, 1H), 1.82 (d, J=11.9Hz, 1H), 1.61-1.48 (m, 1H); LC/MS (ESI) m/z 508.31 [M+H]⁺.

Example 19. Synthesis of Compound 19

Compound 19 was synthesized according to the procedures described inExample 15.

¹H NMR (500 MHz, DMSO-d₆) δ 9.45 (br s, 1H), 8.62 (s, 1H), 7.72 (s, 1H),7.47 (s, 1H), 7.40 (s, 1H), 7.28 (ddd, J=11.2, 8.6, 3.1 Hz, 1H), 7.18(td, J=9.2, 5.6 Hz, 1H), 7.01-6.95 (m, 1H), 6.68-6.52 (m, 2H), 5.33 (brs, 1H), 4.42-3.91 (br m, 4H), 3.75 (s, 3H), 3.23 (br s, 2H), 2.78-2.67(m, 1H), 2.29 (br s, 6H), 1.88 (d, J=12.5 Hz, 1H), 1.78 (d, J=11.3 Hz,1H), 1.58-1.44 (m, 1H); LC/MS (ESI) m/z 565.38 [M+H]⁺.

Example 20. Synthesis of Compound 20

Compound 20 was synthesized according to the procedures described inExample 15.

LC/MS (ESI) m/z 591.40 [M+H]⁺.

Example 21. Synthesis of Compound 21

Compound 21 was synthesized according to the procedures described inExample 15.

LC/MS (ESI) m/z 508.31 [M+H]⁺.

Example 22. Synthesis of Compound 22

Compound 22 was synthesized according to the procedures described inExample 15.

LC/MS (ESI) m/z 494.23 [M+H]⁺.

Example 23. Synthesis of Compound 23

Compound 23 was synthesized according to the procedures described inExample 15.

LC/MS (ESI) m/z 522.27 [M+H]⁺.

Example 24. Synthesis of Compound 24

Compound 24 was synthesized according to the procedures described inExample 15.

LC/MS (ESI) m/z 522.27 [M+H]⁺.

Example 25. Synthesis of Compound 25

Compound 25 was synthesized according to the procedures described inExample 15.

LCMS (ESI) m/z 522.31 [M+H]⁺.

Example 26. Synthesis of Compound 26

Compound 26 was synthesized according to the procedures described inExample 15.

¹NMR (500 MHz, DMSO-d₆) δ 9.99 (br s, 1H), 8.69 (br s, 1H), 7.87 (br s,1H), 7.58-7.50 (m, 2H), 7.49-7.43 (m, 1H), 7.28-7.21 (m, 1H), 7.09-7.03(m, 1H), 6.54-6.37 (m, 1H), 6.13-6.04 (m, 1H), 5.66-5.58 (m, 1H),4.49-4.35 (m, 2H), 3.84 (s, 3H), 3.71-3.40 (m, 3H), 3.36-3.24 (m, 1H),2.92-2.76 (m, 1H), 2.00-1.88 (m, 1H), 1.81-1.68 (m, 1H); LC/MS (ESI) m/z508.27 [M+H]⁺.

Example 27. Synthesis of Compound 27

Compound 27 was synthesized according to the procedures described inExample 15.

¹NMR (500 MHz, DMSO-d₆) δ 9.94-9.66 (m, 1H), 8.67 (br s, 1H), 8.43 (d,J=7.3 Hz, 1H), 7.96-7.82 (m, 1H), 7.65-7.40 (m, 3H), 7.27-7.20 (m, 1H),7.08-7.02 (m, 1H), 6.25 (dd, J=10.1, 17.1 Hz, 1H), 6.08 (dd, J=2.1, 17.1Hz, 1H), 5.58 (dd, J=2.0, 10.2 Hz, 1H), 5.51-5.36 (m, 1H), 4.20-4.09 (m,1H), 3.84 (br s, 3H), 2.99-2.90 (m, 2H), 2.76-2.65 (m, 2H); LC/MS (ESI)m/z 494.19 [M+H]⁺.

Example 28. Synthesis of Compound 28

Compound 28 was synthesized according to the procedures described inExample 15.

¹NMR (500 MHz, DMSO-d₆) δ 10.00-9.71 (m, 1H), 8.68 (br s, 1H), 7.93-7.78(m, 1H), 7.55 (br s, 1H), 7.48-7.42 (m, 2H), 7.26-7.18 (m, 1H),7.09-7.03 (m, 1H), 6.88 (dd, J=10.4, 16.8 Hz, 1H), 6.13 (dd, J=2.4, 16.5Hz, 1H), 5.71-5.68 (m, 1H), 5.68-5.57 (m, 1H), 4.71-4.62 (m, 1H),4.31-4.23 (m, 1H), 3.82 (br s, 3H), 3.12 (t, J=13.0 Hz, 1H), 2.75-2.56(m, 3H), 1.80-1.68 (m, 2H); LC/MS (ESI) m/z 508.27 [M+H]⁺.

Example 29. Synthesis of Compound 29 Step 1: Synthesis of6-(2,4-difluorophenoxy)-8-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one

To a solution of6-(2,4-difluorophenoxy)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one(1.00 g, 3.11 mmol) and potassium carbonate (860 mg, 6.22 mmol) in dryN-methyl-2-pyrrolidone (6 mL) was added iodomethane (291 μL, 4.67 mmol).The resulting mixture was stirred for 2 hr and poured into a cold 0.5 NHCl solution. The precipitate was filtered and dried by blowing nitrogengas to give6-(2,4-difluorophenoxy)-8-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one(879 mg, 84%6) as a light yellow solid.

Step 2: Synthesis of6-(2,4-difluorophenoxy)-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one

6-(2,4-difluorophenoxy)-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-onewas prepared using the same method which was used to synthesizetert-butyl(3-(6-(4-fluorophenoxy)-2-(methylsulfonyl)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)carbamate.The crude product was purified by flash column chromatography(EtOAc:DCM=0:100 to 100:0) yielding the title compound (878 mg, 91%) asa light yellow solid.

Step 3: Synthesis of6-(2,4-difluorophenoxy)-2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one

To a solution of6-(2,4-difluorophenoxy)-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one(878 mg, 2.39 mmol) and 4-fluoro-2-methoxy-5-nitroaniline (1.34 g, 7.17mmol) in dry 2-butanol (8.4 mL) was added trifluoroacetic acid (4.8 mL).The resulting mixture was stirred at 80° C. for 24 hr. Then, thereaction mixture was cooled to room temperature and an excess of diethylether was added. The resulting precipitate was filtered, re-dissolved inDCM and washed repeatedly with sat. NaHCO₃. The organic layer was driedover Na₂SO₄, filtered and concentrated under reduced pressure to give6-(2,4-difluorophenoxy)-2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one(574 mg, 51%) as a light yellow solid.

Step 4: Synthesis of6-(2,4-difluorophenoxy)-2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one

6-(2,4-Difluorophenoxy)-2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one(189 mg, 0.40 mmol) and N,N,N′-trimethylethylenediamine (104 μL, 0.80mmol) were dissolved in dry dioxane (4 mL). The resulting mixture wasstirred at 80° C. for 8 hr. The reaction mixture was cooled to roomtemperature and concentrated under reduced pressure. The residue wasre-dissolved in EtOAc and washed repeatedly with sat. NaHCO₃. Theorganic layer was dried over Na₂SO₄, filtered and concentrated. Thecrude product was used to the next step without further purification.

Step 5: Synthesis of2-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-6-(2,4-difluorophenoxy)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one

6-(2,4-difluorophenoxy)-2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one(222 mg, 0.40 mmol) and tin(II) chloride dihydrate (903 mg, 4.0 mmol)were suspended in EtOAc (9 mL). Subsequently, a catalytic amount ofconc. HCl (37%) was added. The resulting clear solution was stirred at45° C. for 30 min. The reaction mixture was cooled to room temperatureand diluted with an excess of EtOAc. The pH was adjusted to pH 5-6 bydropwise addition of NH₄OH solution, after which the mixture was furtherneutralized to pH 7 by adding an excess of anhydrous Na₂CO₃. Theresulting white precipitate was filtered through a pad of celite andwashed with MeOH. The filtrate was concentrated under reduced pressureand the residue was re-dissolved in a mixture of CHCl₃/iPrOH (4:1) andwashed repeatedly with sat. NaHCO₃. The organic layer was dried overNa₂SO₄, filtered and concentrated. The crude product was used to thenext step without further purification.

Step 6: Synthesis ofN-(5-((6-(2,4-difluorophenoxy)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

N-(5-((6-(2,4-difluorophenoxy)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamidewas synthesized by following the analogous procedure ofN-(3-(6-(4-fluorophenoxy)-2-((1-methyl-1H-pyrazol-4-yl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide.(Compound 29; 32 mg, 14%, three steps, pale yellow solid).

¹H NMR (500 MHz, DMSO-d₆) δ 9.95 (br s, 1H), 8.90 (br s, 1H), 8.69 (s,1H), 8.55 (s, 1H), 7.50-7.44 (m, 2H), 7.25 (td, J=5.5, 9.3 Hz, 1H),7.09-7.04 (m, 1H), 7.01 (s, 1H), 6.50 (br s, 1H), 6.25 (dd, J=1.8, 16.8Hz, 1H), 5.77-5.73 (m, 1H), 3.85 (s, 3H), 3.64 (s, 3H), 3.06-2.91 (m,2H), 2.68 (s, 3H), 2.49-2.05 (br m, 8H); LC/MS (ESI) m/z: 580.69 [M+H]⁺.

Example 30. Synthesis of Compound 30 Step 1: Synthesis of6-(2,4-difluorophenoxy)-2-((4-(2-(dimethylamino)ethoxy)-2-methoxy-5-nitrophenyl)amino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one

6-(2,4-Difluorophenoxy)-2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one(101 mg, 0.21 mmol) and 2-(dimethylamino)ethan-1-ol (63 μL, 0.63 mmol)were dissolved in a mixture of THF/10 N NaOH (3:1, 4 mL). The resultingmixture was stirred at 80° C. for 4 hr. The reaction mixture was cooledto room temperature and concentrated under reduced pressure. The residuewas re-dissolved in DCM and washed repeatedly with water. The organiclayer was dried over Na₂SO₄, filtered and concentrated. The crudeproduct was used to the next step without further purification.

Step 2: Synthesis of2-((5-amino-4-(2-(dimethylamino)ethoxy)-2-methoxyphenyl)amino)-6-(2,4-difluorophenoxy)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one

6-(2,4-Difluorophenoxy)-2-((4-(2-(dimethylamino)ethoxy)-2-methoxy-5-nitrophenyl)amino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one(90 mg, 0.17 mmol), iron powder (47 mg, 0.85 mmol), and ammoniumchloride (91 mg, 1.70 mmol) were suspended in a mixture of THF/MeOH/H₂O(5:2:1, 2 mL). The resulting mixture was vigorously stirred at 80° C.for 30 min. Then, the reaction mixture was cooled to room temperatureand filtered through a pad of celite. The filtrate was concentratedunder reduced pressure and the residue was purified by flash columnchromatography (DCM: 1.75 N NH₃ in MeOH=100:0 to 80:20) to give2-((5-amino-4-(2-(dimethylamino)ethoxy)-2-methoxyphenyl)amino)-6-(2,4-difluorophenoxy)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one(55 mg, 52%, two steps) as a light yellow solid.

Step 3: Synthesis ofN-(5-((6-(2,4-difluorophenoxy)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-2-(2-(dimethylamino)ethoxy)-4-methoxyphenyl)acrylamide

N-(5-((6-(2,4-difluorophenoxy)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-2-(2-(dimethylamino)ethoxy)-4-methoxyphenyl)acrylamidewas synthesized by following the analogous procedure ofN-(3-(6-(4-fluorophenoxy)-2-((1-methyl-1H-pyrazol-4-yl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide(Compound 30; 11 mg, 17%, pale yellow solid).

¹H NMR (500 MHz, DMSO-d₆) δ 9.64 (s, 1H), 8.66 (s, 1H), 8.63 (br s, 1H),8.60 (s, 1H), 7.49-7.43 (m, 2H), 7.23 (td, J=5.5, 9.3 Hz, 1H), 7.05(tdd, J=1.7, 3.0, 8.7 Hz, 1H), 6.93 (s, 1H), 6.47 (dd, J=10.1, 17.1 Hz,1H), 6.22 (dd, J=2.0, 16.9 Hz, 1H), 5.74-5.71 (m, 1H), 4.20 (t, J=5.5Hz, 2H), 3.84 (s, 3H), 3.60 (s, 3H), 2.71-2.60 (m, 2H), 2.31 (br s, 6H);LC/MS (ESI) m/z 567.30 [M+H]⁺.

Example 31. Synthesis of Compound 31

Compound 31 was synthesized according to the procedures described inExample 29 and Example 30.

¹H NMR (500 MHz, DMSO-d₆) δ 8.97 (s, 1H), 8.68 (s, 1H), 8.65 (br s, 1H),8.55 (s, 1H), 7.49-7.44 (m, 2H), 7.24 (td, J=5.6, 9.2 Hz, 1H), 7.08-7.03(m, 1H), 6.87 (s, 1H), 6.60 (dd, J=10.2, 17.2 Hz, 1H), 6.21 (dd, J=1.7,16.9 Hz, 1H), 5.73 (d, J=11.3 Hz, 1H), 3.85 (s, 3H), 3.61 (s, 3H), 2.86(t, J=4.7 Hz, 4H), 2.58-2.51 (m, 4H), 2.25 (s, 3H); LC/MS (ESI) m/z578.27 [M+H]⁺.

Example 32. Synthesis of Compound 32

Compound 32 was synthesized according to the procedures described inExample 29 and Example 30.

¹H NMR (500 MHz, DMSO-d₆) δ 8.95 (s, 1H), 8.67 (br s, 2H), 8.54 (s, 1H),7.49-7.43 (m, 2H), 7.24 (td, J=5.6, 9.4 Hz, 1H), 7.06 (tdd, J=1.7, 3.1,8.6 Hz, 1H), 6.85 (s, 1H), 6.66 (dd, J=10.4, 16.8 Hz, 1H), 6.22 (dd,J=1.8, 17.1 Hz, 1H), 5.72 (d, J=11.9 Hz, 1H), 3.84 (s, 3H), 3.61 (s,3H), 3.03 (d, J=11.0 Hz, 2H), 2.70-2.64 (m, 2H), 2.59-2.50 (m, 4H),2.41-2.21 (m, 5H), 2.15 (s, 3H), 1.84 (d, J=10.1 Hz, 2H), 1.75-1.66 (m,2H); LC/MS (ESI) m/z 661.36 [M+H]⁺.

Example 33. Synthesis of Compound 33

Compound 33 was synthesized according to the procedures described inExample 29 and Example 30.

¹H NMR (500 MHz, DMSO-d₆) δ 9.41 (s, 1H), 8.66 (s, 1H), 8.62 (s, 1H),8.56 (br s, 1H), 7.48-7.43 (m, 2H), 7.23 (td, J=5.5, 9.3 Hz, 1H),7.08-7.03 (m, 1H), 6.91 (s, 1H), 6.56-6.49 (m, 1H), 6.21 (dd, J=1.8,17.1 Hz, 1H), 5.75-5.70 (m, 1H), 4.24 (br s, 2H), 3.84 (s, 3H), 3.58 (s,3H), 2.98-2.79 (m, 2H), 2.75-2.54 (m, 4H), 1.76 (br s, 4H); LC/MS (ESI)m/z 593.58 [M+H]⁺.

Example 34. Synthesis of Compound 34

Compound 34 was synthesized according to the procedures described inExample 29 and Example 30.

¹H NMR (500 MHz, DMSO-d₆) δ 9.33 (s, 1H), 8.63 (s, 1H), 8.54 (s, 1H),7.86 (br s, 1H), 7.48-7.43 (m, 2H), 7.22 (td, J=5.5, 9.3 Hz, 1H),7.07-7.02 (m, 1H), 6.53-6.47 (m, 2H), 6.19 (dd, J=1.8, 17.1 Hz, 1H),5.70-5.67 (m, 1H), 3.83 (s, 3H), 3.55 (s, 3H), 3.39-3.34 (m, 1H),3.24-3.17 (m, 3H), 2.76 (br s, 1H), 2.21 (br s, 6H), 2.12-2.06 (m, 1H),1.79-1.71 (m, 1H); LC/MS (ESI) m/z 592.59 [M+H]⁺.

Example 35. Synthesis of Compound 35

Compound 35 was synthesized according to the procedures described inExample 29 and Example 30.

¹H NMR (500 MHz; DMSO-d₆) δ 9.15 (br s, 1H), 8.65 (s, 1H), 8.62 (s, 1H),8.47 (br s, 1H), 7.48-7.43 (m, 2H), 7.23 (td, J=5.5, 9.3 Hz, 1H), 7.05(tdd, J=1.7, 3.0, 8.7 Hz, 1H), 6.88 (s, 1H), 6.60 (dd, J=10.2, 16.6 Hz,1H), 6.21 (dd, J=2.0, 16.9 Hz, 1H), 5.72-5.70 (m, 1H), 4.23-4.19 (m,2H), 3.84 (s, 3H), 3.57 (s, 3H), 2.89-2.53 (m, 10H), 2.35 (br s, 3H);LC/MS (ESI) m/z 622.64 [M+H]⁺.

Example 36. Synthesis of Compound 80

Compound 80 was synthesized according to the procedures describedherein.

LC-MS m/z: (pos) 517.27 ([M+H]⁺⁾

Example 37. Synthesis of Compound 81

Compound 81 was synthesized according to the procedures describedherein.

¹H NMR (500 MHz, DMSO-d₆) δ 10.45 (s, 1H), 10.02 (s, 1H), 8.71 (s, 1H),7.86 (d, J=7.8 Hz, 1H), 7.77 (br s, 1H), 7.66-7.57 (m, 3H), 7.32 (dd,J=9.2, 5.1 Hz, 1H), 7.22 (td, J=8.5, 3.0 Hz, 1H), 7.15 (d, J=8.8 Hz,1H), 7.11 (s, 1H), 6.78 (s, 1H), 6.44 (dd, J=17.1, 10.0 Hz, 1H), 6.25(dd, J=16.9, 1.9 Hz, 1H), 5.77 (dd, J=10.0, 2.0 Hz, 1H), 3.51 (s, 3H).

Example 38. Synthesis of Compound 82

Compound 82 was synthesized according to the procedures describedherein.

¹H NMR (500 MHz, DMSO-d₆) δ 10.45 (s, 1H), 9.96 (s, 1H), 8.67 (s, 1H),7.88 (d, J=8.0 Hz, 1H), 7.76 (s, 1H), 7.64 (t, J=7.9 Hz, 1H), 7.55-7.42(m, 3H), 7.17 (d, J=7.0 Hz, 1H), 7.11 (s, 1H), 6.77 (s, 1H), 6.44 (dd,J=16.9, 10.2 Hz, 1H), 6.26 (dd, J=16.9, 1.9 Hz, 1H), 5.78 (dd, J=10.4,2.0 Hz, 1H), 3.52 (s, 3H).

Example 39. Synthesis of Compound 83

Compound 83 was synthesized according to the procedures describedherein.

¹H NMR (500 MHz, DMSO-d₆) δ 9.95 (s, 1H), 8.72 (s, 1H), 8.56-8.54 (m,2H), 7.50-7.45 (m, 2H), 7.31-7.23 (m, 2H), 7.07 (tdd, J=1.5, 3.0, 8.6Hz, 1H), 7.03 (d, J=8.9 Hz, 1H), 6.71 (dt, J=5.9, 15.4 Hz, 1H), 6.27 (d,J=15.6 Hz, 1H), 3.83 (s, 3H), 3.64 (s, 3H), 3.10 (d, J=5.8 Hz, 2H), 2.21(s, 6H).

Example 40. Synthesis of Compound 84

Compound 84 was synthesized according to the procedures describedherein.

¹H NMR (500 MHz, DMSO-d₆) δ 10.03 (s, 1H), 8.72 (s, 1H), 8.58-8.55 (m,2H), 7.50-7.45 (m, 2H), 7.31-7.23 (m, 2H), 7.10-7.03 (m, 2H), 6.44 (dd,J=10.1, 16.8 Hz, 1H), 6.24 (dd, J=2.1, 17.1 Hz, 1H), 5.74-5.70 (m, 1H),3.84 (s, 3H), 3.64 (s, 3H).

Example 41. Synthesis of Compound 85

Compound 85 was synthesized according to the procedures describedherein.

¹H NMR (500 MHz; DMSO-d₆) δ 10.12 (br s, 1H), 8.92 (br s, 1H), 8.74 (s,1H), 8.69 (br s, 1H), 7.55 (s, 1H), 7.49 (ddd, J=2.9, 8.7, 11.3 Hz, 1H),7.29 (td, J=5.6, 9.2 Hz, 1H), 7.09 (tdd, J=1.5, 3.0, 8.6 Hz, 1H), 7.01(s, 1H), 6.39 (dd, J=10.1, 17.1 Hz, 1H), 6.28-6.23 (m, 1H), 5.76-5.72(m, 1H), 5.24 (q, J=9.0 Hz, 2H), 3.84 (s, 3H), 2.91-2.85 (m, 2H), 2.71(s, 3H), 2.33-2.27 (m, 2H), 2.21 (br s, 6H).

Example 42. Synthesis of Compound 86

Compound 86 was synthesized according to the procedures describedherein.

¹H NMR (400 MHz, DMSO-d₆) δ 10.45 (s, 1H), 10.27 (s, 1H), 8.82 (s, 1H),8.18 (s, 1H), 7.86 (d, J=8.6 Hz, 1H), 7.78 (s, 1H), 7.68-7.59 (m, 2H),7.51 (ddd, J=9.1, 6.8, 2.0 Hz, 1H), 7.14 (s, 1H), 7.11 (d, J=7.8 Hz,1H), 6.83 (s, 1H), 6.51-6.38 (m, 2H), 6.33-6.21 (m, 2H), 5.80-5.75 (m,1H), 3.54 (s, 3H).

Example 43. Synthesis of Compound 87

Compound 87 was synthesized according to the procedures describedherein.

¹H NMR (400 MHz, DMSO-d₆) δ 10.45 (s, 1H), 10.04 (s, 1H), 8.73 (s, 1H),7.87 (d, J=8.0 Hz, 1H), 7.84-7.72 (m, 3H), 7.68-7.57 (m, 2H), 7.15 (d,J=7.5 Hz, 1H), 7.12 (s, 1H), 6.79 (s, 1H), 6.44 (dd, J=16.9, 10.2 Hz,1H), 6.26 (dd, J=16.8, 1.8 Hz, 1H), 5.79-5.75 (m, 1H), 3.52 (s, 3H).

Example 44. Synthesis of Compound 88

Compound 88 was synthesized according to the procedures describedherein.

¹H NMR (400 MHz, DMSO-d₆) δ 10.44 (s, 1H), 10.02 (s, 1H), 8.73 (s, 1H),7.87 (d, J=8.8 Hz; 1H), 7.77 (br s, 2H), 7.62 (t, 1=7.5 Hz, 1H), 7.45(dt, J=6.0, 2.7 Hz, 1H), 7.40 (d, J=9.0 Hz, 1H), 7.20-7.10 (m, 3H), 6.79(s, 1H), 6.44 (dd, J=17.1, 10.0 Hz, 1H), 6.25 (dd, J=16.9, 1.9 Hz, 1H),5.77 (dd J=10.4, 1.8 Hz, 1H), 3.52 (s, 3H).

Example 45. Synthesis of Compound 89

Compound 89 was synthesized according to the procedures describedherein.

¹H NMR (400 MHz, DMSO-d₆) δ 10.44 (s, 1H), 10.03 (s, 1H), 8.73 (s, 1H),7.86 (d, J=8.0 Hz, 1H), 7.76 (br s, 1H), 7.75 (s, 1H), 7.65-7.59 (m,2H), 7.33 (t, J=8.9 Hz, 1H), 7.25 (d, J=9.5 Hz, 1H), 7.14 (d, J=8.8 Hz,1H), 7.12 (s, 1H), 6.79 (s, 1H), 6.48-6.40 (m, 1H), 6.29-6.22 (m, 1H),5.80-5.75 (m, 1H), 3.52 (s, 3H).

Example 46. Synthesis of Compound 90

Compound 90 was synthesized according to the procedures describedherein.

¹H NMR (400 MHz, DMSO-d₆) δ 10.44 (s, 1H), 10.04 (s, 1H), 8.74 (s, 1H),8.46 (d, J=2.8 Hz; 1H), 8.32 (dd, J=4.8, 1.0 Hz, 1H), 7.90-7.86 (m, 1H),7.84 (s, 1H), 7.76 (br s, 1H), 7.62 (t, J=8.0 Hz, 1H), 7.57 (dd, J=8.5,1.8 Hz, 1H), 7.39 (dd, J=8.4, 4.6 Hz, 1H), 7.16 (d, J=7.8 Hz, 1H), 7.12(s, 1H), 6.79 (s, 1H), 6.44 (dd, J=17.1, 10.0 Hz, 1H), 6.25 (dd, J=17.2,1.9 Hz, 1H), 5.77 (dd, J=10.2, 1.6 Hz, 1H), 3.52 (s, 3H).

Example 47. Synthesis of Compound 91

Compound 91 was synthesized according to the procedures describedherein.

¹H NMR (400 MHz; DMSO-d₆) δ 10.52 (s, 1H), 10.30 (s, 1H), 8.82 (s, 1H),8.26 (s, 1H), 7.86 (s, 1H), 7.83 (d, J=9.0 Hz, 1H), 7.64 (t, J=7.9 Hz,1H), 7.16-7.11 (m, 2H), 6.82 (s, 1H), 6.45 (dd, J=17.2, 10.4 Hz, 1H),6.29-6.21 (m, 1H), 6.20 (d, J=7.5 Hz, 2H), 5.80-5.74 (m, 1H), 3.53 (s,3H).

Example 48. Synthesis of Compound 92

Compound 92 was synthesized according to the procedures describedherein.

¹H NMR (500 MHz, DMSO-d₆) δ 10.01 (s, 1H), 8.71 (s, 1H), 8.67 (s, 1H),8.34 (d, J=2.4 Hz, 1H), 7.50-7.47 (m, 1H), 7.46 (s, 1H), 7.35 (dd,J=2.3, 8.7 Hz, 1H), 7.24 (td, J=5.5, 9.3 Hz, 1H), 7.08 (tdd, J=1.7, 3.0,8.7 Hz, 1H), 7.04 (d, J=8.9 Hz, 1H), 6.44 (dd, J=10.2, 16.9 Hz, 1H),6.24 (dd, J=2.0, 16.9 Hz, 1H), 5.75-5.72 (m, 1H), 4.23 (t, J=6.7 Hz,2H), 3.82 (s, 3H), 3.07-2.98 (m, 4H), 2.62-2.54 (m, 2H), 1.88-1.82 (m,2H).

Example 49. Synthesis of Compound 93

Compound XX was synthesized according to the procedures describedherein.

¹H NMR (500 MHz, DMSO-d₆) δ 10.15 (s, 1H), 8.75 (s, 1H), 8.65 (s, 1H),8.55 (br s, 1H), 7.52 (s, 1H), 7.48 (ddd, J=3.1, 8.7, 11.4 Hz, 1H), 7.27(td, J=5.5, 9.2 Hz, 2H), 7.11-7.06 (m, 2H), 6.47 (dd, J=10.1, 17.1 Hz,1H), 6.27 (dd, J=2.0, 16.9 Hz, 1H), 5.77-5.74 (m, 1H), 4.40 (t, J=6.7Hz, 2H), 3.91-3.78 (m, 7H), 3.07-2.99 (m, 2H), 2.30-2.19 (m, 2H),1.86-1.79 (m, 2H).

Example 50. Synthesis of Compound 94

Compound 94 was synthesized according to the procedures describedherein.

¹H NMR (500 MHz, DMSO-d₆) δ 9.98 (s, 1H), 8.71 (s, 1H), 8.68 (s, 1H),8.31 (d, J=2.4 Hz, 1H), 7.50-7.45 (m, 2H), 7.38 (dd, J=2.4, 8.9 Hz, 1H),7.24 (td, J=5.5, 9.3 Hz, 1H), 7.07 (tdd, J=1.5, 3.1, 8.7 Hz, 1H), 7.04(d, J=8.9 Hz, 1H), 6.41 (dd, J=10.2, 16.9 Hz, 1H), 6.23 (dd, J=2.0, 16.9Hz, 1H), 5.74-5.71 (m, 1H), 4.38 (t, J=6.9 Hz, 2H), 3.82 (s, 3H),2.47-2.42 (m, 2H), 2.07 (s, 6H).

Example 51. Synthesis of Compound 95

Compound 95 was synthesized according to the procedures describedherein.

¹H NMR (500 MHz, DMSO-d₆) δ 10.12 (s, 1H), 8.75 (s, 1H), 8.61 (s, 1H),8.51 (br s, 1H), 7.51 (s, 1H), 7.48 (ddd, J=3.1, 8.7, 11.4 Hz 1H),7.31-7.24 (m, 2H), 7.10-7.05 (m, 2H), 6.46 (dd, J=10.2, 16.9 Hz, 1H),6.25 (dd, J=2.0, 16.9 Hz, 1H), 5.76-5.73 (m, 1H), 4.38 (t, J=7.0 Hz,2H), 3.84 (s, 3H), 2.78-2.67 (m, 2H), 2.43 (br s, 6H), 1.94-1.87 (m,2H).

Example 52. Synthesis of Compound 96

Compound 96 was synthesized according to the procedures describedherein.

¹H NMR (500 MHz, DMSO-d₆) δ 10.04 (s, 1H), 8.74 (s, 2H), 8.67 (s, 1H),7.54-7.40 (m, 2H), 7.26 (td, J=9.3, 5.5, 1H), 7.22 (dd, 1H), 7.11-7.05(m, 1H), 6.99 (d, J=8.8, 1H), 6.44 (dd, J=16.9, 10.1, 1H), 6.24 (dd,J=17.0, 2.0, 1H), 5.72 (dd, J=10.1, 2.0, 1H), 4.87 (ddt, J=7.6, 5.1,2.4, 1H), 3.67 (s, 3H), 2.79-2.73 (m, 1H), 2.68 (dd, J=10.4, 2.0, 1H),2.62 (dd, J=10.5, 5.3, 1H), 2.36-2.21 (m, 5H), 1.89-1.81 (m, 1H). LC-MSm/z: (pos) 548.87 ([M+H]⁺)

Example 53. Synthesis of Compound 97

Compound 97 was synthesized according to the procedures describedherein.

¹H NMR (500 MHz, DMSO-d₆) δ 10.07 (s, 1H), 9.49 (s, 1H), 8.74 (s, 1H),8.56 (s, 1H), 7.55-7.39 (m, 2H), 7.26 (m, =14.8, 8.9, 3.7, 2H), 7.08 (m,J=9.3, 3.1, 1.6, 2H), 6.43 (dd, J=16.9, 10.2, 1H), 6.24 (dd, J=17.0,1.8, 1H), 5.73 (dd, J=10.1, 1.9, 1H), 4.70-4.45 (m, 1H), 3.64 (s, 3H),3.54-3.45 (m, 1H), 3.14-2.97 (m, 1H), 2.78 (s, 3H), 2.34-2.17 (m, 1H),2.21-1.86 (m, 3H), 1.87-1.67 (m, 1H). LC-MS m/z: (pos) 562.79 ([M+H]⁺)

Example 54. Synthesis of Compound 98

Compound 98 was synthesized according to the procedures describedherein.

LC-MS m/z: (pos) 592.87 ([M+H]⁺)

Example 55. Synthesis of Compound 99

Compound 99 was synthesized according to the procedures describedherein.

¹H NMR (500 MHz; DMSO-d₆) δ 12.37 (s, 1H), 10.01 (s, 1H), 8.60 (s, 1H),8.53 (s, 1H), 8.44 (s, 1H), 7.45 (ddd, J=11.5, 8.9, 3.0, 1H), 7.40 (s,1H), 7.24 (td, J=9.3, 5.5, 1H), 7.06 (tdd, J=9.7, 2.9, 1.6, 1H), 6.98(s, 1H), 6.48-6.36 (m, 1H), 6.22 (dd, J=16.9, 1.7, 1H), 5.74 (dd,J=10.2, 1.8, 1H), 3.79 (s, 3H), 2.90 (s, 2H), 2.69 (s, 3H), 2.48-2.05(m, 8H). LC-MS m/z: (pos) 565.92 ([M+H]⁺)

Example 56. Synthesis of Compound 100

Compound 100 was synthesized according to the procedures describedherein.

¹H NMR (500 MHz, DMSO-d₆) δ 10.18 (s, 1H), 8.98 (s, 1H), 8.68 (s, 1H),8.55 (s, 1H), 7.53-7.42 (m, 2H), 7.24 (td, J=9.3, 5.6, 1H), 7.06 (tdd,J=9.8, 3.0, 1.6, 1H), 6.96 (s, 1H), 6.58 (dd, J=16.9, 10.2, 1H), 6.24(dd, J=17.0, 2.0, 1H), 5.72 (dd, J=10.2, 1.9, 1H), 3.84 (s, 3H), 3.64(s, 3H), 2.91-2.85 (m, 2H), 2.74-2.63 (m, 5H), 2.37 (s, 3H). LC-MS m/z:(pos) 565.86 ([M+H]⁺⁾

Example 57. Synthesis of Compound 101

Compound 101 was synthesized according to the procedures describedherein.

¹H NMR (500 MHz, DMSO-d6) δ 10.43 (s, 1H), 10.00 (s, 1H), 8.72 (s, 1H),7.87 (d, J=7.9 Hz, 1H), 7.75 (s, 1H), 7.65-7.57 (m, 2H), 7.51-7.43 (m,1H), 7.36 (td, J=9.2, 5.6 Hz, 1H), 7.18-7.13 (m, 2H), 7.09 (t, J=8.5 Hz,1H), 6.82 (s, 1H), 6.43 (dd, J=17.1, 10.1 Hz, 1H), 6.29-6.21 (m, 1H),5.79-5.75 (m, 1H), 3.88-3.76 (m, 1H), 2.46 (br s, 2H), 2.12 (s, 6H).

Example 58. Synthesis of Compound 102

Compound 102 was synthesized according to the procedures describedherein.

¹H NMR (500 MHz, DMSO-d₆) δ 9.99 (br s, 1H), 8.70 (br s, 1H), 7.87 (brs, 1H), 7.57-7.52 (m, 2H), 7.49-7.43 (m, 1H), 7.23 (td, J=5.8, 9.3 Hz,1H), 7.05 (t, J=7.8 Hz 1H), 6.55-6.38 (m, 1H), 6.14-6.04 (m, 1H), 5.63(dd, J=10.2, 17.2 Hz, 1H), 4.43-4.34 (m, 2H), 3.83 (s, 3H), 3.82-3.78(m, 1H), 3.69-3.52 (m, 2H), 3.52-3.37 (m, 2H), 3.11 (d, J=8.2 Hz, 3H),2.95-2.82 (m, 1H).

Example 59. Synthesis of Compound 103

Compound 103 was synthesized according to the procedures describedherein.

¹H NMR (500 MHz, DMSO-d₆) δ 12.34 (br s, 1H), 9.97 (br s, 1H), 8.42 (brs, 1H), 8.08 (br s, 1H), 7.18 (dd, J=3.1, 9.5 Hz, 1H), 7.08 (s, 1H),7.03-6.94 (m, 3H), 6.54-6.38 (m, 1H), 6.21 (dd, J=1.8, 17.1 Hz, 1H),5.75-5.72 (m, 1H), 3.71 (s, 3H), 3.51 (s, 2H), 3.33 (s, 3H), 3.00-2.86(m, 2H), 2.71 (s, 3H), 2.36 (br s, 6H), 2.20 (s, 3H).

Example 60. Synthesis of Compound 104

Compound 104 was synthesized according to the procedures describedherein.

¹H NMR (500 MHz, DMSO-d₆) δ 9.62 (br s, 1H), 8.84 (br s, 1H), 8.74 (s,1H), 8.69 (s, 1H), 7.91-7.87 (m, 2H), 7.49 (ddd, J=3.4, 8.1, 9.3 Hz,1H), 7.17 (dd, J=4.3, 9.2 Hz, 1H), 7.01 (s, 1H), 6.68-6.50 (m, 1H), 6.25(dd, J=1.8, 16.8 Hz, 1H), 5.77-5.73 (m, 1H), 3.87 (s, 3H), 3.61 (s, 3H),3.32 (s, 3H), 3.24-2.90 (m, 4H), 2.67 (s, 6H).

Example 61. Synthesis of Compound 105

Compound 105 was synthesized according to the procedures describedherein.

¹H NMR (500 MHz, DMSO-d₆) δ 10.35 (br s, 1H), 10.08 (s, 1H), 9.31 (s,1H), 8.78 (s, 1H), 8.26 (s, 1H), 7.51-7.45 (m, 2H), 7.28 (td, J=5.5, 9.3Hz, 1H), 7.11-7.05 (m, 1H), 6.59-6.40 (m, 1H), 6.37-6.32 (m, 1H),5.89-5.86 (m, 1H), 3.77 (s, 3H), 3.02-2.88 (m, 2H), 2.74 (s, 3H),2.45-2.14 (m, 8H).

Example 62. Synthesis of Compound 106

Compound 106 was synthesized according to the procedures describedherein.

¹H NMR (500 MHz, DMSO-d₆) δ 10.31 (s, 1H), 8.59 (s, 1H), 7.70 (d, J=8.5Hz, 1H), 7.60 (t, J=1.8 Hz, 1H), 7.57 (s, 1H), 7.50-7.39 (m, 2H), 7.36(td, J=9.3, 5.5 Hz, 1H), 7.09-6.98 (m, 4H), 6.44 (dd, J=16.9, 10.2 Hz,1H), 6.26 (dd, J=17.1, 1.8 Hz, 1H), 5.77 (dd, J=10.7, 1.8 Hz, 1H).

Example 63. Synthesis of Compound 107

Compound 107 was synthesized according to the procedures describedherein.

¹H NMR (500 MHz, DMSO-d₆) δ 10.29 (s, 1H), 8.70-8.55 (m, 1H), 7.68 (brs, 1H), 7.60 (br s, 1H), 7.56 (br s, 1H), 7.49-7.41 (m, 2H), 7.31 (td,J=9.2, 5.5 Hz, 1H), 7.09-6.98 (m, 2H), 6.43 (dd, J=16.9, 10.2 Hz, 1H),6.25 (dd, J=16.8, 1.8 Hz, 1H), 5.76 (dd, J=10.7, 1.8 Hz, 1H), 2.69 (brs, 1.5H), 2.39 (br s, 1.5H).

Example 64. Synthesis of Compound 108

Compound 108 was synthesized according to the procedures describedherein.

LC-MS m/z: (pos) 565.22 ([M+H]⁺).

Example 65. Synthesis of Compound 109

Compound 109 was synthesized according to the procedures describedherein.

¹H NMR (500 MHz, DMSO-d₆) δ 10.58 (s, 1H), 9.93 (s, 1H), 8.74 (s, 1H),7.50-7.45 (m, 2H), 7.25 (dt, J=9.3, 4.7, 1H), 7.08 (tt, J=8.7, 2.2, 1H),6.73 (s, 1H), 6.45 (dd, J=17.0, 10.2, 1H), 6.23 (dd, J=17.1, 1.8, 1H),5.70 (dd, J=10.2, 1.8, 1H), 3.63 (s, 3H), 3.59 (s, 3H). LC-MS m/z: (pos)453.91 ([M+H]⁺).

Example 66. Synthesis of Compound 110

Compound 110 was synthesized according to the procedures describedherein.

¹H NMR (500 MHz, DMSO-d₆) δ 8.57 (s, 1H), 7.50 (d, J=5.8 Hz, 1H),7.46-7.41 (m, 1H), 7.21-7.16 (m, 3H), 7.05-7.00 (m, 1H), 6.65-6.46 (m,1H), 6.13 (ddd, J=2.4, 11.3, 16.8 Hz, 1H), 5.69-5.62 (m, 1H), 4.31 (ddd,J=3.8, 9.0, 12.8 Hz, 1H), 4.15 (dd, J=6.3, 13.0 Hz, 1H), 3.98 (dd,J=4.9, 11.6 Hz, 1H), 3.75-3.61 (m, 2H), 3.57-3.44 (m, 2H), 3.11 (d,J=10.4 Hz, 3H), 2.89-2.75 (m, 1H).

Example 67. Synthesis of Compound 111

Compound 111 was synthesized according to the procedures describedherein.

¹H NMR (500 MHz, DMSO-d₆) δ 9.44 (s, 1H), 9.29 (s, 1H), 8.69 (s, 1H),8.54 (s, 1H), 7.50-7.42 (m, 2H), 7.25 (td, J=9.3, 5.5 Hz, 1H), 7.11-7.03(m, 1H), 6.96 (s, 1H), 3.87 (s, 3H), 3.62 (s, 3H), 3.35-3.13 (m, 4H),2.77 (br s, 6H), 2.61 (s, 3H), 2.42 (q, J=7.3 Hz, 2H), 1.12 (t, J=7.5Hz, 3H).

Example 68. Synthesis of Compound 112

Compound 112 was synthesized according to the procedures describedherein.

¹H NMR (500 MHz, DMSO-d₆) δ 10.76 (d, J=2.7 Hz, 1H), 8.88 (d, J=1.2 Hz,1H), 7.54-7.47 (m, 2H), 7.37-7.31 (m, 1H), 7.15-7.09 (m, 1H), 6.60-6.45(m, 1H), 6.11 (ddd, J=2.3, 7.5, 16.8 Hz, 1H), 5.68-5.60 (m, 1H), 4.41(dd, J=8.5, 13.1 Hz, 1H), 4.28 (td, J=7.0, 13.6 Hz, 1H), 4.03 (dd,J=5.2, 11.3 Hz, 1H), 3.77-3.60 (m, 2H), 3.57-3.44 (m, 2H), 3.10 (d,J=3.7 Hz, 3H), 2.96-2.84 (m, 1H), 2.23 (d, J=6.7 Hz, 3H).

Example 69. Synthesis of Compound 113

Compound 113 was synthesized according to the procedures describedherein.

¹H NMR (400 MHz, DMSO-d₆) δ 10.12 (s, 1H), 9.06 (s, 1H), 8.74 (s, 1H),8.43 (s, 1H), 8.27 (s, 1H), 7.55-7.45 (m, 2H), 7.30-7.21 (m, 1H),7.11-7.03 (m, 1H), 6.52-6.43 (m, 1H), 6.33-6.25 (m, 1H), 5.84-5.79 (m,1H), 3.76 (s, 3H), 2.98-2.94 (m, 2H), 2.74 (s, 3H), 2.50-2.43 (m, 2H),2.24 (s, 6H).

Example 70. Synthesis of Compound 114

Compound 114 was synthesized according to the procedures describedherein.

¹H NMR (400 MHz, DMSO-d₆) δ 10.04 (s, 1H), 9.52 (s, 1H), 8.99 (br s,1H), 8.31-8.23 (m, 1H), 7.52-7.44 (m, 2H), 7.24 (td, J=9.3, 5.6 Hz, 1H),7.07 (t, J=8.7 Hz, 1H), 6.72 (dd, J=16.9, 10.3 Hz, 1H), 6.27 (dd,J=17.0, 1.6 Hz, 1H), 5.77 (dd, J=8.7 Hz, 1H), 4.43 (t, J=6.1 Hz, 1H),3.64 (s, 3H), 2.70 (t, J=6.1 Hz, 1H), 2.24 (s, 6H).

Example 71. Synthesis of Compound 115

Compound 115 was synthesized according to the procedures describedherein.

LC-MS m/z: (pos) 578.26 ([M+H]⁺).

Example 72. Synthesis of Compound 116

Compound 116 was synthesized according to the procedures describedherein.

¹H NMR (400 MHz, DMSO-d₆) δ 10.22 (s, 1H), 10.00 (s, 1H), 8.87 (br s,1H), 8.72 (s, 1H), 7.50 (s, 1H), 7.49-7.42 (m, 1H), 7.29 (d, J=8.8 Hz,1H), 7.27-7.20 (m, 1H), 7.10-7.30 (m, 1H), 6.40 (dd, J=16.8, 10.0 Hz,1H), 6.27 (dd, J=17.1, 2.0 Hz, 1H), 5.78 (dd, J=10.4, 2.0 Hz, 1H), 3.68(s, 3H), 2.81 (t, J=5.5 Hz, 2H), 2.66 (s, 3H), 2.27 (t, J=5.4 Hz, 2H),2.19 (s, 6H).

Example 73. Synthesis of Compound 117

Compound 117 was synthesized according to the procedures describedherein.

¹H NMR (400 MHz, DMSO-d₆) δ 10.31 (br s, 1H), 10.01 (s, 1H), 8.83 (s,1H), 8.18 (br s, 1H), 7.58-7.41 (m, 3H), 7.29-7.21 (m, 2H), 7.11-7.02(m, 1H), 6.41 (dd, J=16.9, 10.2 Hz, 1H), 6.25 (dd, J=16.8, 2.0 Hz, 1H),5.80-5.73 (m, 1H), 3.65 (s, 3H), 2.57 (t, J=7.2 Hz, 2H), 2.16 (s, 6H),2.12 (t, J=6.7 Hz, 2H), 1.69 (t, J=6.7 Hz, 2H).

Example 74. Synthesis of Compound 118

Compound 118 was synthesized according to the procedures describedherein.

¹H NMR (500 MHz, DMSO-d₆) δ 10.59 (s, 1H), 10.20 (s, 1H), 8.76 (s, 1H),8.70 (s, 1H), 7.59-7.36 (m, 3H), 7.26 (td, J=9.3, 5.5, 1H), 7.12-7.03(m, 1H), 6.45-6.22 (m, 2H), 5.82 (dd, 1H), 3.70 (s, 3H), 3.01 (s, 2H),2.75 (s, 3H), 2.45-1.95 (m, 8H). LC-MS m/z: (pos) 567.86 ([M+H]⁺).

Example 75. Synthesis of Compound 119

Compound 119 was synthesized according to the procedures describedherein.

¹H NMR (500 MHz, DMSO-d₆) δ 10.54 (s, 1H), 10.17 (s, 1H), 8.75 (s, 1H),8.57 (s, 1H), 7.66-7.43 (m, 3H), 7.26 (td, J=9.2, 5.4, 1H), 7.08 (ddt,J=10.8, 8.7, 2.0, 1H), 6.43-6.26 (m, 2H), 5.84 (dd, 1H), 4.25-4.06 (m,2H), 3.69 (s, 3H), 2.76-2.53 (m, 2H), 2.45-2.08 (m, 6H). LC-MS m/z:(pos) 554.83 ([M+H]⁺).

Example 76. Synthesis of Compound 120

Compound 120 was synthesized according to the procedures describedherein.

¹H NMR (500 MHz, DMSO-d₆) δ 10.03 (s, 1H), 8.67 (s, 1H), 7.89 (s, 1H),7.65 (s, 1H), 7.54-7.40 (m, 2H), 7.26-7.18 (m, 1H), 7.06 (t, J=9.0, 1H),6.60 (dd, J=16.7, 10.3, 1H), 6.21 (dd, J=16.7, 2.4, 1H), 5.72 (dd,J=10.2, 2.4, 1H), 4.31 (s, 2H), 4.24-4.12 (m, 1H), 3.64 (s, 3H),3.48-3.38 (m, 2H), 1.88-1.61 (m, 4H). LC-MS m/z: (pos) 507.88 ([M+H]⁺).

Example 77. Synthesis of Compound 121

Compound 121 was synthesized according to the procedures describedherein.

¹H NMR (500 MHz, DMSO-d₆) δ 9.11 (s, 1H), 8.63 (s, 1H), 7.82 (d, 1H),7.45 (m, J=14.2, 7.3, 3.0, 2H), 7.21 (td, J=9.3, 5.4, 1H), 7.09-7.01 (m,1H), 6.60 (dd, J=16.7, 10.3, 1H), 6.19 (dd, J=16.7, 2.4, 1H), 5.70 (dd,J=10.3, 2.4, 1H), 4.31 (s, 1H), 4.24-4.01 (m, 2H), 3.82 (d, 3H), 3.55(s, 3H), 3.52-3.44 (m, 2H), 1.97-1.71 (m, 4H). LC-MS m/z: (pos) 537.78([M+H]⁺).

Example 78. Synthesis of Compound 122

Compound 122 was synthesized according to the procedures describedherein.

LC-MS m/z: (pos) 537.84 ([M+H]⁺).

Example 79. Synthesis of Compound 123

Compound 123 was synthesized according to the procedures describedherein.

LC-MS m/z: (pos) 551.82 ([M+H]⁺).

Example 80. Synthesis of Compound 124

Compound 124 was synthesized according to the procedures describedherein.

¹H NMR (500 MHz, DMSO-d₆) δ 10.23 (s, 1H), 8.92 (s, 1H), 8.75 (s, 1H),8.69 (s, 1H), 8.10 (d, J=2.1, 1H), 7.52-7.46 (m, 2H), 7.27 (td, J=9.4,5.6, 1H), 7.08 (tdd, J=8.6, 3.0, 1.6, 1H), 6.44 (dd, J=17.0, 10.2, 1H),6.27 (dd, J=16.9, 2.0, 1H), 5.77 (dd, J=10.1, 2.0, 1H), 3.93 (s, 3H),3.65 (s, 3H). LC-MS m/z: (pos) 480.92 ([M+H]⁺).

Example 81. Synthesis of Compound 125

Compound 125 was synthesized according to the procedures describedherein.

LC-MS m/z: (pos) 591.87 ([M+H]⁺)

Example 82. Synthesis of Compound 126

Compound 126 was synthesized according to the procedures describedherein.

¹H NMR (500 MHz, DMSO-d₆) δ 10.24 (br s, 1H), 8.58 (s, 1H), 7.55 (s,1H), 7.47-7.40 (m, 2H), 7.34-7.27 (m, 1H), 7.24-7.18 (m, 1H), 7.06-6.97(m, 5H), 6.82 (dd, J=16.5, 10.1 Hz, 1H), 6.17 (d, J=16.5 Hz, 1H), 6.06(d, J=10.1 Hz, 1H).

Example 83. Synthesis of Compound 127

Compound 127 was synthesized according to the procedures describedherein.

LC-MS m/z: (pos) 563.22 ([M+H]⁺), retention time=0.83

Example 84. Synthesis of Compound 128

Compound 128 was synthesized according to the procedures describedherein.

¹H NMR (400 MHz, DMSO-d₆) δ 9.50 (s, 1H), 8.69 (s, 1H), 8.52 (s, 1H),8.32 (s, 1H), 8.06 (s, 1H), 7.52-7.41 (m, 2H), 7.24 (td, J=9.3, 5.4 Hz,1H), 7.06 (t, J=8.2 Hz, 1H), 6.93 (s, 1H), 6.50 (dd, J=16.9, 10.3 Hz,1H), 6.21 (dd, J=17.1, 2.0 Hz, 1H), 5.75-5.68 (m, 1H), 3.88 (s, 3H),3.58 9s, 3H), 2.87 (d, J=11.0 Hz, 1H), 2.72-2.61 (m, 1H), 2.19 (s, 3H),1.92 (t, J=10.3 Hz, 1H), 1.78-1.59 (m, 4H).

Example 85. Synthesis of Compound 129

Compound 129 was synthesized according to the procedures describedherein.

¹H NMR (500 MHz, DMSO-d₆) δ 10.05 (s, 1H), 9.54 (s, 1H), 9.38 (s, 1H),8.72 (d, J=15.4, 2H), 7.58-7.49 (m, 2H), 7.30 (d, J=8.7, 1H), 7.24-7.18(m, 2H), 7.09 (dd, J=9.1, 4.3, 2H), 6.74 (dd, J=16.9, 10.2, 1H), 6.31(dd J=16.9, 1.9, 1H), 5.79 (dd J=10.2, 2.0, 1H), 3.67 (s, 3H), 3.28-3.24(m, 2H), 3.22-3.17 (m, 2H), 2.80 (d, J=4.4, 6H), 2.55 (s, 3H). LC-MSm/z: (pos) 532.31 ([M+H]⁺).

Example 86. Synthesis of Compound 130

Compound 130 was synthesized according to the procedures describedherein.

¹H NMR (500 MHz; DMSO-d₆) δ 9.87 (s, 1H), 8.91 (s, 1H), 8.69 (s, 1H),8.53 (s, 1H), 7.51 (s, 1H), 7.19 (t, J=8.8, 2H), 7.09 (dd, J=9.1, 4.3,2H), 7.02 (s, 1H), 6.54-6.43 (m, 1H), 6.25 (dd, J=16.9, 2.0, 1H), 5.75(dd, J=9.9, 2.0, 1H), 3.86 (s, 3H), 3.64 (s, 3H), 3.00 (s, 2H),2.75-2.55 (m, 5H), 2.39 (s, 6H). LC-MS m/z: (pos) 562.33 ([M+H]⁺).

Example 87. Synthesis of Compound 131

Compound 131 was synthesized according to the procedures describedherein.

¹H NMR (500 MHz, DMSO-d₆) δ 10.03 (s, 1H), 8.99 (s, 1H), 8.68 (s, 1H),8.48 (s, 1H), 7.41 (s, 1H), 7.17 (d, J=8.2 Hz, 2H), 7.02 (s, 1H), 6.95(d, J=8.4 Hz, 2H), 6.46-6.38 (m, 1H), 6.24 (dd, J=16.9, 2.1 Hz, 1H),5.74 (dd, J=10.1, 2.1 Hz, 1H), 3.85 (s, 3H), 3.65 (s, 3H), 2.91 (s, 2H),2.70 (s, 3H), 2.42-2.19 (m, 11H). LC-MS m/z: (pos) 558.32 ([M+H]⁺).

Example 88. Synthesis of Compound 132

Compound 132 was synthesized according to the procedures describedherein.

¹H NMR (500 MHz, DMSO-d₆) δ 10.21 (s, 1H), 8.83 (s, 1H), 8.70 (s, 1H),8.54 (s, 1H), 7.54 (s, 1H), 7.36 (t, J=7.9 Hz, 2H), 7.10 (t, J=7.3 Hz,1H), 7.03 (d, J=8.0 Hz, 2H), 6.98 (s, 1H), 6.25 (dd, J=16.9, 2.1 Hz,1H), 5.72 (dd, J=10.0, 2.1 Hz, 1H), 3.87 (s, 3H), 3.63 (s, 3H), 3.21 (s,3H), 2.96-2.51 (m, 10H). LC-MS m/z: (pos) 544.34 ([M+H]⁺).

Example 89. Synthesis of Compound 133

Compound 133 was synthesized according to the procedures describedherein.

¹H NMR (400 MHz, DMSO-d₆) δ 10.16 (s, 1H), 8.70 (s, 1H), 8.52 (s, 1H),8.36 (d, J=19.1 Hz, 1H), 7.49-7.44 (m, 2H), 7.24 (td, J=9.3, 5.5 Hz,1H), 7.06 (ddd, J=10.9, 6.6, 2.3 Hz 1H), 6.94 (s, 1H), 6.40 (dd, J=17.0,10.1 Hz, 1H), 6.22 (dd, J=17.0, 2.1 Hz, 1H), 5.73 (dd, J=10.1, 2.1 Hz,1H), 3.85 (s, 3H), 3.60 (s, 3H), 2.59 (t, J=7.1 Hz, 2H), 2.17-2.13 (m,8H), 1.76-1.70 (m, 2H).

Example 90. Synthesis of Compound 134

Compound 134 was synthesized according to the procedures describedherein.

LC-MS m/z: (pos) 596.24 ([M+H]⁺), retention time=0.94

Example 91. Synthesis of Compound 135

Compound 135 was synthesized according to the procedures describedherein.

LC-MS m/z: (pos) 598.25 ([M+H]⁺), retention time=0.92

Example 92. Synthesis of Compound 136

Compound 136 was synthesized according to the procedures describedherein.

LC-MS m/z: (pos) 598.25 ([M+H]⁺), retention time=0.89

Example 93. Synthesis of Compound 137

Compound 137 was synthesized according to the procedures describedherein.

¹H NMR (400 MHz, DMSO-d₆) δ 10.09 (s, 1H), 9.00 (s, 1H), 8.71 (s, 1H),8.58 (s, 1H), 7.67 (s, 1H), 7.39 (t, J=9.0 Hz, 1H), 7.34 (dd, J=6.1, 3.1Hz, 1H), 7.09 (dt, J=9.2, 3.3 Hz, 1H), 7.03 (s, 1H), 6.39 (dd, J=16.7,9.9 Hz, 1H), 6.23 (dd, J=16.8, 1.8 Hz, 1H), 5.77-5.72 (m, 1H), 3.85 (s,3H), 3.63 (s, 3H), 2.87 (t, J=5.8 Hz, 2H), 2.71 (s, 3H), 2.30 (t, J=5.5Hz, 2H), 2.20 (s, 6H). LC-MS m/z: (pos) 596.25 ([M+H]⁺), retentiontime=0.97

Example 94. Synthesis of Compound 138

Compound 138 was synthesized according to the procedures describedherein.

¹H NMR (500 MHz, DMSO-d₆) δ 12.41 (s, 1H), 9.89 (br s, 1H), 8.42 (br s,1H), 8.00 (br s, 1H), 7.62 (td, J=6.4, 8.5 Hz, 1H), 7.48 (td, J=2.7, 9.3Hz, 1H), 7.24-7.18 (m, 2H), 6.98 (s, 1H), 6.76-6.55 (m, 1H), 6.22 (dd,J=2.0, 16.9 Hz, 1H), 5.75-5.71 (m, 1H), 3.71 (s, 3H), 3.51 (s, 3H), 3.34(s, 3H), 3.23-2.84 (m, 4H), 2.65 (s, 6H).

Example 95. Synthesis of Compound 139

Compound 139 was synthesized according to procedures similar to theprocedures described herein.

LC-MS m/z: (pos) 563.91

Example 96. Synthesis of Compound 140

Compound 140 was synthesized according to procedures similar to theprocedures described herein.

¹H NMR (500 MHz, DMSO-d₆) δ 10.09 (s, 1H), 8.73 (s, 1H), 8.66 (s, 1H),7.91 (s, 1H), 7.55 (ddd, J=11.5, 8.9, 3.0, 1H), 7.43 (td, J=9.2, 5.6,1H), 7.19 (tdd, J=9.2, 3.1, 1.6, 1H), 7.14 (s, 1H), 6.97 (s, 1H),6.48-6.38 (m, 1H), 6.24 (d, J=16.8, 1H), 5.77 (d, J=11.1, 1H), 3.85 (s,3H), 2.93 (s, 2H), 2.68 (s, 3H), 2.28 (s, 8H).

Example 97. Synthesis of Compound 141

Compound 141 was synthesized according to the procedures describedherein.

¹H NMR (500 MHz, DMSO-d₆) δ 10.04 (br s, 1H), 9.08 (br s, 1H), 8.62 (s,1H), 8.16 (s, 1H), 7.61 (s, 1H), 7.48 (td, J=9.0, 6.1 Hz, 1H), 7.41-7.33(m, 1H), 7.15-7.08 (m, 1H), 7.01 (s, 1H), 6.84 (d, J=1.8 Hz, 1H),6.49-6.35 (m, 1H), 6.29-6.25 (m, 1H), 5.75-5.72 (m, 1H), 3.86 (s, 3H),3.76 (s, 3H), 2.91 (br s, 2H), 2.69 (s, 3H), 2.46-2.08 (m, 8H).

Example 98. Synthesis of Compound 142

Compound 142 was synthesized according to the procedures describedherein.

¹H NMR (500 MHz, DMSO-d₆) δ 9.69 (br s, 1H), 8.79 (br s, 1H), 8.60 (s,1H), 8.20 (s, 1H), 7.58 (s, 1H), 7.48 (td, J=9.0, 6.1 Hz, 1H), 7.42-7.33(m, 1H), 7.16-7.07 (m, 1H), 6.92 (s, 1H), 6.83 (d, J=1.8 Hz, 1H), 6.47(dd, J=16.9, 10.2 Hz, 1H), 6.28-6.18 (m, 1H), 5.78-5.69 (m, 1H), 4.18(t, J=5.3 Hz, 2H), 3.85 (s, 3H), 3.71 (s, 3H), 2.63 (s, 2H), 2.31 (m,6H).

Example 99. Synthesis of Compound 143

Compound 143 was synthesized according to procedures similar to theprocedures described herein.

¹H NMR (400 MHz, CDCl₃) δ 9.00 (s, 1H), 8.45 (s, 1H), 7.55 (s, 1H),7.37-7.22 (m, 3H), 7.17-7.08 (m, 1H), 6.56 (dd, J=16.7, 10.4 Hz, 1H),6.40 (d, J=17.1 Hz; 1H), 6.01 (d, J=10.3 Hz, 1H), 4.28 (br s, 2H), 4.07(s, 3H), 3.47 (s, 3H), 3.44 (s, 3H), 3.42-3.34 (m, 2H), 2.94 (m, 6H).

Example 100. Synthesis of Compound 144

Compound 144 was synthesized according to procedures similar to theprocedures described herein.

LC-MS m/z: (pos) 579.26 ([M+H]⁺), retention time=0.79

Example 101. Biological Assays

Proliferation Inhibition Assays:

Cell growth inhibition was assessed by MTS assay for Ba/F3, DFCI58-229,and DFCI127c cells, or by Cell Titer Glo Luminescent Cell viabilityassay (Promega®) for DFCI362JC cells. 3000 Ba/F3 cells were seeded forper well in 96-well plates, and were exposed to representative compoundsof the application (3.3 nM to 10 μM) for 72 hours. For DFCI58-229,DFCI127c, and DFCI362JC cells. 5000 cells were seeded per well. Allexperimental points included 6 to 12 wells. Data were normalized tountreated cells and displayed graphically using GraphPad Prism (GraphPadSoftware, Inc.). The growth curves were fitted using a nonlinearregression model with sigmoidal dose response.

Western Blot Analysis:

Cells were plated at 5×10⁵ cells per well in 6-well plates and treatedwith representative compounds of the application the following day.After 6 hours of treatment, cells were washed with PBS and lysed withNP40 buffer (Calbiochem®) supplemented with Complete™ Mini proteaseinhibitor and PhosSTOP™ phosphatase inhibitors (Roche®). Lysates wereseparated by SDS-PAGE gel, transferred to nitrocellulose membranes, andprobed with the following antibodies: phospho-EGFR(Tyr1068) (3777),total EGFR (2232), p-Akt(Ser473) (4060), total Akt (9272),p-ERK(Thr202/Tyr204) (4370), total ERK (9102) (Cell Signaling), andHSP90 (SC-7947) (Santa Cruz Biotechnology®).

Example 102. Assessing the Activity of the Representative Compounds ofthe Present Application in Inhibiting EFGR and HER2

Activities of representative compounds of the present application ininhibiting EGFR and HER2 were tested by MTS assay (for Ba/F3 cell,DFCI58-229 cell, and DFCI127c cells) or by CellTiter-Glo® luminescentcell viability assay (for DFCI362JC cells). For assays with Ba/F3 cells,3000 cells were seeded for per well in 96-well plates and were exposedto indicated compounds with a concentration of 3.3 to 10 μM for 72hours. For assays with DFCI58-229 cell, DFCI127c cell, or DFCI362JCcell, 5000 cells were seeded per well in 96-well plates and were exposedto indicated compounds with a concentration of 3.3 to 10 μM for 72hours.

Western blot analysis was then performed on the cells. The cells wereplated at 5×10⁵ cells per well in 6-well plates and treated with theindicated concentrations of the compound. After 6 hours of treatment,cells were washed with PBS and lysed with NP40 buffer (Calbiochem)supplemented with Complete Mini protease inhibitor and PhosSTOPphosphatase inhibitors (Roche). Lysates were then separated by SDS-PAGEgel, transferred to nitrocellulose membranes, and probed with thefollowing antibodies: phospho-EGFR(Tyr1068) (3777), total EGFR (2232),p-Akt(Ser473) (4060), total Akt (9272), p-ERK(Thr202/Tyr204) (4370),total ERK (9102) (Cell Signaling), and HSP90 (SC-7947) (Santa CruzBiotechnology).

Activities of representative compounds of the present application areshown in FIGS. 1, 2A-C, and 3, and Tables 8-11 below.

TABLE 8 EC₅₀ values in proliferation inhibition assays against wild-typeor insertion mutants EGFRs transformed Ba/F3 cells (A = over 1000 nM; B= 600 to 1000 nM; C = 200 to 600 nM; D = below 200 nM). Com- EGFRtransformed Ba/F3 cells pound wild- # type InsGY InsSVD InsASV InsHHInsH InsNPG 1 D D D D D D D 9 D D D D D D D 3 D D D D C C D 4 D D D D DD D 5 D D D D D D D 6 D D D D D D D 7 D D D D D C D 15 D D D D C A D 17D D D D C B D 23 D D D D D C D 24 D D D D C C D 8 D D D D D D D 29 D D DD D D D 10 C C C D C B D 26 D D D D B A D 82 D D D D 85 D D D D 87 D D B88 D D C 89 D D C 94 D D C A 99 D D D C 102 D D D C 105 C A A A 106 D DD C 110 C D 111 A A A A 112 D D 113 D D D B 116 D D D 117 D C A 125 D DD B 127 A A 128 C B 129 D C A 130 D D D 131 D D C 132 D D D 134 D D D C135 D D D C 136 D D D C 140 D C C B 141 D D D C 142 D D D B 144 D D D C

TABLE 9 EC₅₀ values in proliferation inhibition assays against wild-typeor insertion mutants HER2s transformed Ba/F3 cells (A = over 500 nM; B =250 to 500 nM; C = 100 to 250 nM; D = below 100 nM). HER2 transformedBa/F3 cells Compound # wild-type InsYVMA InsVC InsGSP InsWLV 1 D D D D C2 D D D D D 3 D D C D C 4 D D D D D 5 D D C D C 6 D D C D D 7 D D C D C15 D D D D C 17 D D D D B 23 D D D D C 24 D D D D C 8 D D D D D 29 D D DD D 10 D D B D B 26 D A B D C 140 D D B 141 D D D 142 D D C 144 D D C

TABLE 10 EC₅₀ values in proliferation inhibition assays againstwild-type or insertion mutants HER2s transformed Ba/F3 cells (A = over1000 nM; B = 600 to 1000 nM; C = 200 to 600 nM; D = below 200 nM). HER2transformed Ba/F3 cells Compound # wild-type InsYVMA InsWLV 82 D D D 85D D D 87 D D D 88 D D C 89 D D D 94 D D C 99 D D D 102 D D D 105 C B B106 D D D 110 D D 111 A A A 112 C C 113 D D D 116 D D D 117 D D C 125 DD C 127 A A 128 C D 129 D D B 130 D D D 131 D D D 132 D D D 134 D D D135 D D D 136 D D D 137 D D D

TABLE 11 EC₅₀ values in proliferation inhibition assays against mutantEGFRs transformed Ba/F3 cells (A = below or equal to 100 nM; B = above100 mM). L858R Exon19del T90M/L858R T790M/exon19del gefitinib A A B Bosimertinib A A A A Compound 2 A A A A

EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain, usingno more than routine experimentation, numerous equivalents to thespecific embodiments described specifically herein. Such equivalents areintended to be encompassed in the scope of the following claims.

The invention claimed is:
 1. A compound of Formula X:

or a pharmaceutically acceptable salt thereof, wherein: X₁ is N; X₂ isCR₆; X₃ is —NR₂—C(O)— or —N═CR₂—; X₄ is NH, O, or S; R₁ is H, C₁-C₄alkyl, C(O)—(C₁-C₄ alkyl), C₃-C₈ cycloalkyl, heterocyclyl comprising oneor two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O,and S, phenyl, or heteroaryl comprising one or two 5- or 6-memberedrings and 1-4 heteroatoms selected from N, O, and S, wherein thecycloalkyl, heterocyclyl, phenyl, or heteroaryl is optionallysubstituted with one or more R_(a1); and R₂ is Q-R₂′, wherein Q is(CH₂)₀₋₃ and R₂′ is C₃-C₈ cycloalkyl, heterocyclyl comprising one 4- to7-membered ring and 1-3 heteroatoms selected from N, O, and S, phenyl,or heteroaryl comprising one 5- or 6-membered ring and 1-3 heteroatomsselected from N, O, and S, wherein the cycloalkyl, heterocyclyl, phenyl,or heteroaryl is substituted with one or more R_(b1), provided that whenQ is (CH₂)₀, R₂′ is pyrrolidinyl, and R₃ is phenyl or phenyl substitutedwith halogen, then R₁ is not substituted phenyl; or R₁ is phenyl orheteroaryl comprising one 5- or 6-membered ring and 1-3 heteroatomsselected from N, O, and S, wherein the phenyl or heteroaryl issubstituted with two or three R_(a2); and R₂ is H, NH₂, C₁-C₄ alkyl, orC₃-C₆ cycloalkyl, wherein the alkyl or cycloalkyl is optionallysubstituted with one or more R_(b2); R₃ is C₆-C₁₀ aryl or heteroarylcomprising one or two 5- or 6-membered rings and 1-4 heteroatomsselected from N, O, and S, wherein the aryl or heteroaryl is optionallysubstituted with one or more R₇; R₄, R₅, and R₆ are each independently Hor C₁-C₄ alkyl; each R₇ is independently C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, OH, halogen, CN, or NR_(n3)R_(n4); eachR_(a1) is independently C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkoxy, OH, halogen, NH—C(O)—(C₂-C₄ alkenyl), NR_(n3)R_(n4),O—(CH₂)₁₋₄—NR_(n1)R_(n2), NR_(n1)—(CH₂)₁₋₄—NR_(n1)R_(n2), C₃-C₈cycloalkyl, heterocyclyl comprising one or two 4- to 6-membered ringsand 1-4 heteroatoms selected from N, O, and S, phenyl, or heteroarylcomprising one or two 5- or 6-membered rings and 1-4 heteroatomsselected from N, O, and S, wherein the alkyl, cycloalkyl, heterocyclyl,phenyl, or heteroaryl is optionally substituted with one or more R₁₁;each R_(b1) is independently W, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy, C₁-C₆ haloalkoxy, OH, halogen, or NR_(n3)R_(n4), wherein atleast one R_(b1) is W, or when the at least one R_(b1) is bonded to anitrogen atom in a heterocyclyl ring comprising at least one nitrogenatom, R_(b1) is C(O)R₉; each R_(a2) is independently W, NH—C(O)—(C₁-C₄alkyl), C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy,OH, halogen, NR_(n3)R_(n4), O—(CH₂)₀₋₄—NR_(n1)R_(n2),NR_(n1)—(CH₂)₁₋₄—NR_(n1)R_(n2), C₃-C₈ cycloalkyl, heterocyclylcomprising one or two 4- to 6-membered rings and 1-4 heteroatomsselected from N, O, and S, phenyl, or heteroaryl comprising one or two5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S,wherein the alkyl, cycloalkyl, heterocyclyl, phenyl, or heteroaryl isoptionally substituted with one or more R₁₁, wherein at least one R_(a2)is W; each R_(b2) is independently C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy, C₁-C₆ haloalkoxy, OH, halogen, NR_(n3)R_(n4), or heterocyclylcomprising one 4- to 6-membered rings and 1 or 2 heteroatoms selectedfrom N, O, and S; each R₈ is independently H or C₁-C₄ alkyl; each R₉ isindependently C₂-C₄ alkenyl optionally substituted with one or more R₁₀;each R₁₀ is independently NR_(n3)R_(n4); each R₁₁ is independently C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, OH, halogen, CN,NR_(n3)R_(n4), C₃-C₈ cycloalkyl, or heterocyclyl comprising one or two4- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S,wherein the cycloalkyl or heterocyclyl is optionally substituted withone or more C₁-C₆ alkyl, halogen, or C(O)—(C₂-C₄ alkenyl); each R_(n1)and each R_(n2) are independently H or C₁-C₄ alkyl, or R_(n1) andR_(n2), together with the nitrogen atom to which they are bonded, form a4- to 7-membered heterocyclyl ring comprising 1 to 3 heteroatomsselected from N, O, and S, wherein the heterocyclyl is optionallysubstituted with one or more C₁-C₆ alkyl; each R_(n3) and each R_(n4)are independently H or C₁-C₄ alkyl; W is NR₈C(O)R₉, C(O)R₉, or is offormula:

L₃ is a bond or an optionally substituted C₁-C₄ hydrocarbon chain,optionally wherein one or more carbon units of the hydrocarbon chain areindependently replaced with —C═O—, —O—, —S—, —NR_(L3a)—,—NR_(L3a)C(═O)—, —C(═O)NR_(L3a)—, —SC(═O)—, —C(═O)S—, —OC(═O)—,—C(═O)O—, —NR_(L3a)C(═S)—, —C(═S)NR_(L3a)—, trans-CR_(L3b)═CR_(L3b)—,cis-CR_(L3b)═CR_(L3b)—, —C≡C—, —S(═O)—, —S(═O)O—, —OS(═O)—,—S(═O)NR_(L3a)—, —NR_(L3a)S(═O)—, —S(═O)₂—, —S(═O)₂O—, —OS(═O)₂—,—S(═O)₂NR_(L3a)—, or —NR_(L3a)S(═O)₂—; R_(L3a) is H, optionallysubstituted C₁-C₆ alkyl, or a nitrogen protecting group; each R_(L3b) isindependently H, halogen, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₂-C₆ alkenyl, optionally substituted C₂-C₆ alkynyl,optionally substituted C₃-C₈ cycloalkyl, optionally substitutedheterocyclyl comprising one or two 5- or 6-membered rings and 1-4heteroatoms selected from N, O, and S, optionally substituted C₆-C₁₀aryl, or optionally substituted heteroaryl comprising one or two 5- or6-membered rings and 1-4 heteroatoms selected from N, O, and S, or twoR_(L3b) groups are joined to form an optionally substituted C₃-C₈carbocycle or optionally substituted 4- to 7-membered heterocyclyl ringcomprising 1 to 3 heteroatoms selected from N, O, and S; L₄ is a bond oran optionally substituted C₁-C₆ hydrocarbon chain; each of R_(E1),R_(E2), and R_(E3) is independently H, halogen, optionally substitutedC₁-C₆ alkyl, optionally substituted C₂-C₆ alkenyl, optionallysubstituted C₂-C₆ alkynyl, optionally substituted C₃-C₈ cycloalkyl,optionally substituted heterocyclyl comprising one or two 5- or6-membered rings and 1-4 heteroatoms selected from N, O, and S,optionally substituted C₆-C₁₀ aryl, or optionally substituted heteroarylcomprising one or two 5- or 6-membered rings and 1-4 heteroatomsselected from N, O, and S, CN, CH₂OR_(EE), CH₂N(R_(EE))₂, CH₂SR_(EE),OR_(EE), N(R_(EE))₂, Si(R_(EE))₃, or SR_(EE), or R_(E1) and R_(E3), orR_(E2) and R_(E3), or R_(E1) and R_(E2) are joined to form an optionallysubstituted C₃-C₈ carbocycle or optionally substituted 4- to 7-memberedheterocyclyl ring comprising 1 to 3 heteroatoms selected from N, O, andS; each R_(EE) is independently H, optionally substituted C₁-C₆ alkyl,optionally substituted C₁-C₆ alkoxy, optionally substituted C₂-C₆alkenyl, optionally substituted C₂-C₆ alkynyl, optionally substitutedC₃-C₈ cycloalkyl, optionally substituted heterocyclyl comprising one ortwo 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, andS, optionally substituted C₆-C₁₀ aryl, or optionally substitutedheteroaryl comprising one or two 5- or 6-membered rings and 1-4heteroatoms selected from N, O, and S, or two R_(EE) groups are joinedto form an optionally substituted 4- to 7-membered heterocyclyl ringcomprising 1 to 3 heteroatoms selected from N, O, and S; R_(E4) is aleaving group; R_(E5) is halogen; R_(E6) is H, optionally substitutedC₁-C₆ alkyl, or a nitrogen protecting group; each Y is independently O,S, or NR_(E7); R_(E7) is H, optionally substituted C₁-C₆ alkyl, or anitrogen protecting group; a is 1 or 2; and each z is independently 0,1, 2, 3, 4, 5, or
 6. 2. The compound of claim 1, being of Formula I:

or a pharmaceutically acceptable salt thereof, wherein: R₁ is C₃-C₈cycloalkyl, heterocyclyl comprising one or two 5- or 6-membered ringsand 1-4 heteroatoms selected from N, O, and S, phenyl, or heteroarylcomprising one or two 5- or 6-membered rings and 1-4 heteroatomsselected from N, O, and S, wherein the cycloalkyl, heterocyclyl, phenyl,or heteroaryl is optionally substituted with one or more R_(a1); and R₂is Q-R₂′, wherein Q is (CH₂)₀₋₃ and R₂′ is C₃-C₈ cycloalkyl,heterocyclyl comprising one 4- to 7-membered ring and 1-3 heteroatomsselected from N, O, and S, phenyl, or heteroaryl comprising one 5- or6-membered ring and 1-3 heteroatoms selected from N, O, and S, whereinthe cycloalkyl, heterocyclyl, phenyl, or heteroaryl is substituted withone or more R_(b1), provided that when Q is (CH₂)₀, R₂′ is pyrrolidinyl,and R₃ is phenyl or phenyl substituted with halogen, then R₁ is notsubstituted phenyl; or R₁ is phenyl or heteroaryl comprising one 5- or6-membered ring and 1-3 heteroatoms selected from N, O, and S, whereinthe phenyl or heteroaryl is substituted with two or three R_(a2); and R₂is C₁-C₄ alkyl or C₃-C₆ cycloalkyl, wherein the alkyl or cycloalkyl isoptionally substituted with one or more R_(b2); R₃ is C₆-C₁₀ aryl orheteroaryl comprising one or two 5- or 6-membered rings and 1-4heteroatoms selected from N, O, and S, wherein the aryl or heteroaryl isoptionally substituted with one or more R₇; R₄, R₅, and R₆ are eachindependently H or C₁-C₄ alkyl; each R₇ is independently C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, OH, halogen, CN, orNR_(n3)R_(n4); each R_(a1) is independently C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, OH, halogen, NR_(n3)R_(n4),O—(CH₂)₁₋₄—NR_(n1)R_(n2), NR_(n1)—(CH₂)₁₋₄—NR_(n1)R_(n2), C₃-C₈cycloalkyl, heterocyclyl comprising one or two 4- to 6-membered ringsand 1-4 heteroatoms selected from N, O, and S, phenyl, or heteroarylcomprising one or two 5- or 6-membered rings and 1-4 heteroatomsselected from N, O, and S, wherein the cycloalkyl, heterocyclyl, phenyl,or heteroaryl is optionally substituted with one or more R₁₁; eachR_(b1) is independently W, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkoxy, OH, halogen, or NR_(n3)R_(n4), wherein at least oneR_(b1) is W, or when the at least one R_(b1) is bonded to a nitrogenatom in a heterocyclyl ring comprising at least one nitrogen atom,R_(b1) is C(O)R₉; each R_(a2) is independently W, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, OH, halogen, NR_(n3)R_(n4),O—(CH₂)₁₋₄—NR_(n1)R_(n2), NR_(n1)—(CH₂)₁₋₄—NR_(n1)R_(n2), C₃-C₈cycloalkyl, heterocyclyl comprising one or two 4- to 6-membered ringsand 1-4 heteroatoms selected from N, O, and S, phenyl, or heteroarylcomprising one or two 5- or 6-membered rings and 1-4 heteroatomsselected from N, O, and S, wherein the cycloalkyl, heterocyclyl, phenyl,or heteroaryl is optionally substituted with one or more R₁₁, wherein atleast one R_(a2) is W; each R_(b2) is independently C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, OH, halogen, orNR_(n3)R_(n4); each R₈ is independently H or C₁-C₄ alkyl; each R₉ isindependently C₂-C₄ alkenyl optionally substituted with one or more R₁₀;each R₁₀ is independently NR_(n3)R_(n4); each R₁₁ is independently C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, OH, halogen,NR_(n3)R_(n4), C₃-C₈ cycloalkyl, or heterocyclyl comprising one or two5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S,wherein the cycloalkyl or heterocyclyl is optionally substituted withone or more C₁-C₆ alkyl; each R_(n1) and each R_(n2) are independently Hor C₁-C₄ alkyl, or R_(n1) and R_(n2), together with the nitrogen atom towhich they are bonded, form a 4- to 7-membered heterocyclyl ringcomprising 1 to 3 heteroatoms selected from N, O, and S, wherein theheterocyclyl is optionally substituted with one or more C₁-C₆ alkyl;each R_(n3) and each R_(n4) are independently H or C₁-C₄ alkyl; W isNR₈C(O)R₉, C(O)R₉, or is of formula:

L₃ is a bond or an optionally substituted C₁-C₄ hydrocarbon chain,optionally wherein one or more carbon units of the hydrocarbon chain areindependently replaced with —C═O—, —O—, —S—, —NR_(L3a)—,—NR_(L3a)C(═O)—, —C(═O)NR_(L3a)—, —SC(═O)—, —C(═O)S—, —OC(═O)—,—C(═O)O—, —NR_(L3a)C(═S)—, —C(═S)NR_(L3a)—, trans-CR_(L3b)═CR_(L3b)—,cis-CR_(L3b)═CR_(L3b)—, —C≡C—, —S(═O)—, —S(═O)O—, —OS(═O)—,—S(═O)NR_(L3a)—, —NR_(L3a)S(═O)—, —S(═O)₂—, —S(═O)₂O—, —OS(═O)₂—,—S(═O)₂NR_(L3a)—, or —NR_(L3a)S(═O)₂—; R_(L3a) is H, optionallysubstituted C₁-C₆ alkyl, or a nitrogen protecting group; each R_(L3b) isindependently H, halogen, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₂-C₆ alkenyl, optionally substituted C₂-C₆ alkynyl,optionally substituted C₃-C₈ cycloalkyl, optionally substitutedheterocyclyl comprising one or two 5- or 6-membered rings and 1-4heteroatoms selected from N, O, and S, optionally substituted C₆-C₁₀aryl, or optionally substituted heteroaryl comprising one or two 5- or6-membered rings and 1-4 heteroatoms selected from N, O, and S, or twoR_(L3b) groups are joined to form an optionally substituted C₃-C₈carbocycle or optionally substituted 4- to 7-membered heterocyclyl ringcomprising 1 to 3 heteroatoms selected from N, O, and S; L₄ is a bond oran optionally substituted C₁-C₆ hydrocarbon chain; each of R_(E1),R_(E2), and R_(E3) is independently H, halogen, optionally substitutedC₁-C₆ alkyl, optionally substituted C₂-C₆ alkenyl, optionallysubstituted C₂-C₆ alkynyl, optionally substituted C₃-C₈ cycloalkyl,optionally substituted heterocyclyl comprising one or two 5- or6-membered rings and 1-4 heteroatoms selected from N, O, and S,optionally substituted C₆-C₁₀ aryl, or optionally substituted heteroarylcomprising one or two 5- or 6-membered rings and 1-4 heteroatomsselected from N, O, and S, CN, CH₂OR_(EE), CH₂N(R_(EE))₂, CH₂SR_(EE),OR_(EE), N(R_(EE))₂, Si(R_(EE))₃, or SR_(EE), or R_(E1) and R_(E3), orR_(E2) and R_(E3), or R_(E1) and R_(E2) are joined to form an optionallysubstituted C₃-C₈ carbocycle or optionally substituted 4- to 7-memberedheterocyclyl ring comprising 1 to 3 heteroatoms selected from N, O, andS; each R_(EE) is independently H, optionally substituted C₁-C₆ alkyl,optionally substituted C₁-C₆ alkoxy, optionally substituted C₂-C₆alkenyl, optionally substituted C₂-C₆ alkynyl, optionally substitutedC₃-C₈ cycloalkyl, optionally substituted heterocyclyl comprising one ortwo 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, andS, optionally substituted C₆-C₁₀ aryl, or optionally substitutedheteroaryl comprising one or two 5- or 6-membered rings and 1-4heteroatoms selected from N, O, and S, or two R_(EE) groups are joinedto form an optionally substituted 4- to 7-membered heterocyclyl ringcomprising 1 to 3 heteroatoms selected from N, O, and S; R_(E4) is aleaving group; R_(E5) is halogen; R_(E6) is H, optionally substitutedC₁-C₆ alkyl, or a nitrogen protecting group; each Y is independently O,S, or NR_(E7); R_(E7) is H, optionally substituted C₁-C₆ alkyl, or anitrogen protecting group; a is 1 or 2; and each z is independently 0,1, 2, 3, 4, 5, or
 6. 3. The compound of claim 1, wherein R₂ is Q-R₂′;and R₁ is C₃-C₈ cycloalkyl optionally substituted with one or moreR_(a1), heterocyclyl comprising one or two 5- or 6-membered rings and1-4 heteroatoms selected from N, O, and S optionally substituted withone or more R_(a1), phenyl optionally substituted with one or moreR_(a1), or heteroaryl comprising one or two 5- or 6-membered rings and1-4 heteroatoms selected from N, O, and S optionally substituted withone or more R_(a1).
 4. The compound of claim 1, wherein Q is (CH₂)₀ or(CH₂)₁.
 5. The compound of claim 1, wherein R₂′ is substituted with one,two, or more R_(b1), and one R_(b1) is NR₈C(O)R₉.
 6. The compound ofclaim 1, wherein R₁ is phenyl substituted with two or three R_(a2) orheteroaryl comprising one 5- or 6-membered ring and 1-3 heteroatomsselected from N, O, and S substituted with two or three R_(a2); and R₂is C₁-C₄ alkyl or C₃-C₆ cycloalkyl, wherein the alkyl or cycloalkyl isoptionally substituted with one or more R_(b2).
 7. The compound of claim1, wherein R₁ is substituted with two or three R_(a2), and one R_(a2) isNR₈C(O)R₉.
 8. The compound of claim 1, wherein the compound is ofFormula Ia2:

or a pharmaceutically acceptable salt thereof.
 9. The compound of claim1, wherein the compound is of Formula Ib1:

or a pharmaceutically acceptable salt thereof, wherein: m is 0, 1, or 2;and n is 1 or
 2. 10. The compound of claim 1, wherein the compound is ofFormula Ic or Ic1:

or a pharmaceutically acceptable salt thereof, wherein: m is 0, 1, 2, or3; and p2 is 0, 1, 2, or
 3. 11. The compound of claim 1, being ofFormula Ie1 or Ie2:

or a pharmaceutically acceptable salt thereof.
 12. The compound of claim11, wherein R_(a1) is independently R_(a1a), or R_(a1b), wherein R_(a1a)is C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, orhalogen; and R_(a1b) is


13. The compound of claim 12, being of Formula Ie3 or Ie4:

or a pharmaceutically acceptable salt thereof.
 14. The compound of claim1, wherein R₂ is


15. The compound of claim 1, selected from the group consisting of


16. The compound of claim 1, being of any one of Formulae Xa, Xb, andXc:

or a pharmaceutically acceptable salt thereof.
 17. The compound of claim16, being selected from the group consisting of


18. A pharmaceutical composition comprising a compound of claim 1, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.
 19. A method of treating lung cancer, comprisingadministering to a subject in need thereof an effective amount of acompound claim 1, or a pharmaceutically acceptable salt thereof.
 20. Themethod of claim 19, wherein the cancer is non-small cell lung cancer.